Impact of socioeconomic deprivation on rate and cause of death in severe mental illness

Background: Socioeconomic status has important associations with disease-specific mortality in the general population. Although individuals with Severe Mental Illnesses (SMI) experience significant premature mortality, the relationship between socioeconomic status and mortality in this group remains under investigated.<p></p> Aims: To assess the impact of socioeconomic status on rate and cause of death in individuals with SMI (schizophrenia and bipolar disorder) relative to the local (Glasgow) and wider (Scottish) populations.<p></p> Methods: Cause and age of death during 2006-2010 inclusive for individuals with schizophrenia or bipolar disorder registered on the Glasgow Psychosis Clinical Information System (PsyCIS) were obtained by linkage to the Scottish General Register Office (GRO). Rate and cause of death by socioeconomic status, measured by Scottish Index of Multiple Deprivation (SIMD), were compared to the Glasgow and Scottish populations.<p></p> Results: Death rates were higher in people with SMI across all socioeconomic quintiles compared to the Glasgow and Scottish populations, and persisted when suicide was excluded. Differences were largest in the most deprived quintile (794.6 per 10,000 population vs. 274.7 and 252.4 for Glasgow and Scotland respectively). Cause of death varied by socioeconomic status. For those living in the most deprived quintile, higher drug-related deaths occurred in those with SMI compared to local Glasgow and wider Scottish population rates (12.3% vs. 5.9%, p = <0.001 and 5.1% p = 0.002 respectively). A lower proportion of deaths due to cancer in those with SMI living in the most deprived quintile were also observed, relative to the local Glasgow and wider Scottish populations (12.3% vs. 25.1% p = 0.013 and 26.3% p = <0.001). The proportion of suicides was significantly higher in those with SMI living in the more affluent quintiles relative to Glasgow and Scotland (54.6% vs. 5.8%, p = <0.001 and 5.5%, p = <0.001). Discussion and conclusions: Excess mortality in those with SMI occurred across all socioeconomic quintiles compared to the Glasgow and Scottish populations but was most marked in the most deprived quintiles when suicide was excluded as a cause of death. Further work assessing the impact of socioeconomic status on specific causes of premature mortality in SMI is needed

APP controls the formation of PI(3,5)P2 vesicles through its binding of the PIKfyve complex

Phosphoinositides are signalling lipids that are crucial for major signalling events as well as established regulators of membrane trafficking. Control of endosomal sorting and endosomal homeostasis requires phosphatidylinositol-3-phosphate (PI(3)P) and phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2), the latter a lipid of low abundance but significant physiological relevance. PI(3,5)P2 is formed by phosphorylation of PI(3)P by the PIKfyve complex which is crucial for maintaining endosomal homeostasis. Interestingly, loss of PIKfyve function results in dramatic neurodegeneration. Despite the significance of PIKfyve, its regulation is still poorly understood. Here we show that the Amyloid Precursor Protein (APP), a central molecule in Alzheimer’s disease, associates with the PIKfyve complex (consisting of Vac14, PIKfyve and Fig4) and that the APP intracellular domain directly binds purified Vac14. We also show that the closely related APP paralogues, APLP1 and 2 associate with the PIKfyve complex. Whether APP family proteins can additionally form direct protein–protein interaction with PIKfyve or Fig4 remains to be explored. We show that APP binding to the PIKfyve complex drives formation of PI(3,5)P2 positive vesicles and that APP gene family members are required for supporting PIKfyve function. Interestingly, the PIKfyve complex is required for APP trafficking, suggesting a feedback loop in which APP, by binding to and stimulating PI(3,5)P2 vesicle formation may control its own trafficking. These data suggest that altered APP processing, as observed in Alzheimer’s disease, may disrupt PI(3,5)P2 metabolism, endosomal sorting and homeostasis with important implications for our understanding of the mechanism of neurodegeneration in Alzheimer’s disease

Lateral adhesion drives reintegration of misplaced cells into epithelial monolayers.

Cells in simple epithelia orient their mitotic spindles in the plane of the epithelium so that both daughter cells are born within the epithelial sheet. This is assumed to be important to maintain epithelial integrity and prevent hyperplasia, because misaligned divisions give rise to cells outside the epithelium. Here we test this assumption in three types of Drosophila epithelium; the cuboidal follicle epithelium, the columnar early embryonic ectoderm, and the pseudostratified neuroepithelium. Ectopic expression of Inscuteable in these tissues reorients mitotic spindles, resulting in one daughter cell being born outside the epithelial layer. Live imaging reveals that these misplaced cells reintegrate into the tissue. Reducing the levels of the lateral homophilic adhesion molecules Neuroglian or Fasciclin 2 disrupts reintegration, giving rise to extra-epithelial cells, whereas disruption of adherens junctions has no effect. Thus, the reinsertion of misplaced cells seems to be driven by lateral adhesion, which pulls cells born outside the epithelial layer back into it. Our findings reveal a robust mechanism that protects epithelia against the consequences of misoriented divisions.The authors are grateful to R. Nieuwburg, the St Johnston group, and other Gurdon Institute members for suggestions. We thank the Bloomington Stock Center, J. Knoblich, and the TRiP at Harvard Medical School (NIH/NIGMS R01-GM084947) for fly stocks. We thank N. Lowe for technical assistance. This work was supported by a Wellcome Trust Principal Fellowship to D.St.J. (080007), and by core support from the Wellcome Trust (092096) and Cancer Research UK (A14492). D.T.B. was supported by a Marie Curie Fellowship and the Wellcome Trust. H.E.L. was supported by a Herchel Smith Studentship.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ncb324

An in vitro approach to study effects of prebiotics and probiotics on the faecal microbiota and selected immune parameters relevant to the elderly

The aging process leads to alterations of gut microbiota and modifications to the immune response, such changes may be associated with increased disease risk. Prebiotics and probiotics can modulate microbiome changes induced by aging; however, their effects have not been directly compared. The aim of this study was to use anaerobic batch culture fermenters to assess the impact of various fermentable carbohydrates and microorganisms on the gut microbiota and selected immune markers. Elderly volunteers were used as donors for these experiments to enable relevance to an aging population. The impact of fermentation supernatants on immune markers relevant to the elderly were assessed in vitro. Levels of IL-1β, IL-6, IL-8, IL-10 and TNF-α in peripheral blood mononuclear cell culture supernatants were measured using flow cytometry. Trans-galactooligosaccharides (B-GOS) and inulin both stimulated bifidobacteria compared to other treatments (p<0.05). Fermentation supernatants taken from faecal batch cultures supplemented with B-GOS, inulin, B. bifidum, L. acidophilus and Ba. coagulans inhibited LPS induced TNF-α (p<0.05). IL-10 production, induced by LPS, was enhanced by fermentation supernatants from faecal batch cultures supplemented with B-GOS, inulin, B. bifidum, L. acidophilus, Ba. coagulans and Bac. thetaiotaomicron (p<0.05). To conclude, prebiotics and probiotics could lead to potentially beneficial effects to host health by targeting specific bacterial groups, increasing saccharolytic fermentation and decreasing inflammation associated with aging. Compared to probiotics, prebiotics led to greater microbiota modulation at the genus level within the fermenters

A Whole-Genome SNP Association Study of NCI60 Cell Line Panel Indicates a Role of Ca2+ Signaling in Selenium Resistance

Epidemiological studies have suggested an association between selenium intake and protection from a variety of cancer. Considering this clinical importance of selenium, we aimed to identify the genes associated with resistance to selenium treatment. We have applied a previous methodology developed by our group, which is based on the genetic and pharmacological data publicly available for the NCI60 cancer cell line panel. In short, we have categorized the NCI60 cell lines as selenium resistant and sensitive based on their growth inhibition (GI50) data. Then, we have utilized the Affymetrix 125K SNP chip data available and carried out a genome-wide case-control association study for the selenium sensitive and resistant NCI60 cell lines. Our results showed statistically significant association of four SNPs in 5q33–34, 10q11.2, 10q22.3 and 14q13.1 with selenium resistance. These SNPs were located in introns of the genes encoding for a kinase-scaffolding protein (AKAP6), a membrane protein (SGCD), a channel protein (KCNMA1), and a protein kinase (PRKG1). The knock-down of KCNMA1 by siRNA showed increased sensitivity to selenium in both LNCaP and PC3 cell lines. Furthermore, SNP-SNP interaction (epistasis) analysis indicated the interactions of the SNPs in AKAP6 with SGCD as well as SNPs in AKAP6 with KCNMA1 with each other, assuming additive genetic model. These genes were also all involved in the Ca2+ signaling, which has a direct role in induction of apoptosis and induction of apoptosis in tumor cells is consistent with the chemopreventive action of selenium. Once our findings are further validated, this knowledge can be translated into clinics where individuals who can benefit from the chemopreventive characteristics of the selenium supplementation will be easily identified using a simple DNA analysis

A New Fluorescence-Based Method Identifies Protein Phosphatases Regulating Lipid Droplet Metabolism

In virtually every cell, neutral lipids are stored in cytoplasmic structures called lipid droplets (LDs) and also referred to as lipid bodies or lipid particles. We developed a rapid high-throughput assay based on the recovery of quenched BODIPY-fluorescence that allows to quantify lipid droplets. The method was validated by monitoring lipid droplet turnover during growth of a yeast culture and by screening a group of strains deleted in genes known to be involved in lipid metabolism. In both tests, the fluorimetric assay showed high sensitivity and good agreement with previously reported data using microscopy. We used this method for high-throughput identification of protein phosphatases involved in lipid droplet metabolism. From 65 yeast knockout strains encoding protein phosphatases and its regulatory subunits, 13 strains revealed to have abnormal levels of lipid droplets, 10 of them having high lipid droplet content. Strains deleted for type I protein phosphatases and related regulators (ppz2, gac1, bni4), type 2A phosphatase and its related regulator (pph21 and sap185), type 2C protein phosphatases (ptc1, ptc4, ptc7) and dual phosphatases (pps1, msg5) were catalogued as high-lipid droplet content strains. Only reg1, a targeting subunit of the type 1 phosphatase Glc7p, and members of the nutrient-sensitive TOR pathway (sit4 and the regulatory subunit sap190) were catalogued as low-lipid droplet content strains, which were studied further. We show that Snf1, the homologue of the mammalian AMP-activated kinase, is constitutively phosphorylated (hyperactive) in sit4 and sap190 strains leading to a reduction of acetyl-CoA carboxylase activity. In conclusion, our fast and highly sensitive method permitted us to catalogue protein phosphatases involved in the regulation of LD metabolism and present evidence indicating that the TOR pathway and the SNF1/AMPK pathway are connected through the Sit4p-Sap190p pair in the control of lipid droplet biogenesis

Activation Status of Wnt/ß-Catenin Signaling in Normal and Neoplastic Breast Tissues: Relationship to HER2/neu Expression in Human and Mouse

Wnt/ß-catenin signaling is strongly implicated in neoplasia, but the role of this pathway in human breast cancer has been controversial. Here, we examined Wnt/ß-catenin pathway activation as a function of breast cancer progression, and tested for a relationship with HER2/neu expression, using a human tissue microarray comprising benign breast tissues, ductal carcinoma in situ (DCIS), and invasive carcinomas. Cores were scored for membranous ß-catenin, a key functional component of adherens junctions, and for nucleocytoplasmic ß-catenin, a hallmark of Wnt/ß-catenin pathway activation. Only 82% of benign samples exhibited membrane-associated ß-catenin, indicating a finite frequency of false-negative staining. The frequency of membrane positivity was similar in DCIS samples, but was significantly reduced in carcinomas (45%, P<0.001), consistent with loss of adherens junctions during acquisition of invasiveness. Negative membrane status in cancers correlated with higher grade (P = 0.04) and estrogen receptor-negative status (P = 0.03), both indices of poor prognosis. Unexpectedly, a substantial frequency of nucleocytoplasmic ß-catenin was observed in benign breast tissues (36%), similar to that in carcinomas (35%). Positive-staining basal nuclei observed in benign breast may identify putative stem cells. An increased frequency of nucleocytoplasmic ß-catenin was observed in DCIS tumors (56%), suggesting that pathway activation may be an early event in human breast neoplasia. A correlation was observed between HER2/neu expression and nucleocytoplasmic ß-catenin in node-positive carcinomas (P = 0.02). Furthermore, cytoplasmic ß-catenin was detected in HER2/neu-induced mouse mammary tumors. The Axin2NLSlacZ mouse strain, a previously validated reporter of mammary Wnt/ß-catenin signaling, was utilized to define in vivo transcriptional consequences of HER2/neu-induced ß-catenin accumulation. Discrete hyperplastic foci observed in mammary glands from bigenic MMTV/neu, Axin2NLSlacZ mice, highlighted by robust ß-catenin/TCF signaling, likely represent the earliest stage of mammary intraepithelial neoplasia in MMTV/neu mice. Our study thus provides provocative evidence for Wnt/ß-catenin signaling as an early, HER2/neu-inducible event in breast neoplasia

Patient-Reported Measures for Person-Centered Coordinated Care: A Comparative Domain Map and Web-Based Compendium for Supporting Policy Development and Implementation

BACKGROUND: Patient-reported measure (PRM) questionnaires were originally used in research to measure outcomes of intervention studies. They have now evolved into a diverse family of tools measuring a range of constructs including quality of life and experiences of care. Current health and social care policy increasingly advocates their use for embedding the patient voice into service redesign through new models of care such as person-centered coordinated care (P3C). If chosen carefully and used efficiently, these tools can help improve care delivery through a variety of novel ways, including system-level feedback for health care management and commissioning. Support and guidance on how to use these tools would be critical to achieve these goals. OBJECTIVE: The objective of this study was to develop evidence-based guidance and support for the use of P3C-PRMs in health and social care policy through identification of PRMs that can be used to enhance the development of P3C, mapping P3C-PRMs against an existing model of domains of P3C, and integration and organization of the information in a user-friendly Web-based database. METHODS: A pragmatic approach was used for the systematic identification of candidate P3C-PRMs, which aimed at balancing comprehensiveness and feasibility. This utilized a number of resources, including existing compendiums, peer-reviewed and gray literature (using a flexible search strategy), and stakeholder engagement (which included guidance for relevant clinical areas). A subset of those candidate measures (meeting prespecified eligibility criteria) was then mapped against a theoretical model of P3C, facilitating classification of the construct being measured and the subsequent generation of shortlists for generic P3C measures, specific aspects of P3C (eg, communication or decision making), and condition-specific measures (eg, diabetes, cancer) in priority areas, as highlighted by stakeholders. RESULTS: In total, 328 P3C-PRMs were identified, which were used to populate a freely available Web-based database. Of these, 63 P3C-PRMs met the eligibility criteria for shortlisting and were classified according to their measurement constructs and mapped against the theoretical P3C model. We identified tools with the best coverage of P3C, thereby providing evidence of their content validity as outcome measures for new models of care. Transitions and medications were 2 areas currently poorly covered by existing measures. All the information is currently available at a user-friendly web-based portal (p3c.org.uk), which includes all relevant information on each measure, such as the constructs targeted and links to relevant literature, in addition to shortlists according to relevant constructs. CONCLUSIONS: A detailed compendium of P3C-PRMs has been developed using a pragmatic systematic approach supported by stakeholder engagement. Our user-friendly suite of tools is designed to act as a portal to the world of PRMs for P3C, and have utility for a broad audience, including (but not limited to) health care commissioners, managers, and researchers.BACKGROUND: Patient-reported measure (PRM) questionnaires were originally used in research to measure outcomes of intervention studies. They have now evolved into a diverse family of tools measuring a range of constructs including quality of life and experiences of care. Current health and social care policy increasingly advocates their use for embedding the patient voice into service redesign through new models of care such as person-centered coordinated care (P3C). If chosen carefully and used efficiently, these tools can help improve care delivery through a variety of novel ways, including system-level feedback for health care management and commissioning. Support and guidance on how to use these tools would be critical to achieve these goals. OBJECTIVE: The objective of this study was to develop evidence-based guidance and support for the use of P3C-PRMs in health and social care policy through identification of PRMs that can be used to enhance the development of P3C, mapping P3C-PRMs against an existing model of domains of P3C, and integration and organization of the information in a user-friendly Web-based database. METHODS: A pragmatic approach was used for the systematic identification of candidate P3C-PRMs, which aimed at balancing comprehensiveness and feasibility. This utilized a number of resources, including existing compendiums, peer-reviewed and gray literature (using a flexible search strategy), and stakeholder engagement (which included guidance for relevant clinical areas). A subset of those candidate measures (meeting prespecified eligibility criteria) was then mapped against a theoretical model of P3C, facilitating classification of the construct being measured and the subsequent generation of shortlists for generic P3C measures, specific aspects of P3C (eg, communication or decision making), and condition-specific measures (eg, diabetes, cancer) in priority areas, as highlighted by stakeholders. RESULTS: In total, 328 P3C-PRMs were identified, which were used to populate a freely available Web-based database. Of these, 63 P3C-PRMs met the eligibility criteria for shortlisting and were classified according to their measurement constructs and mapped against the theoretical P3C model. We identified tools with the best coverage of P3C, thereby providing evidence of their content validity as outcome measures for new models of care. Transitions and medications were 2 areas currently poorly covered by existing measures. All the information is currently available at a user-friendly web-based portal (p3c.org.uk), which includes all relevant information on each measure, such as the constructs targeted and links to relevant literature, in addition to shortlists according to relevant constructs. CONCLUSIONS: A detailed compendium of P3C-PRMs has been developed using a pragmatic systematic approach supported by stakeholder engagement. Our user-friendly suite of tools is designed to act as a portal to the world of PRMs for P3C, and have utility for a broad audience, including (but not limited to) health care commissioners, managers, and researchers

The accessibility and acceptability of self-management support interventions for men with long term conditions: a systematic review and meta-synthesis of qualitative studies

Background: Self-management support interventions can improve health outcomes, but their impact is limited by the numbers of people able or willing to access them. Men’s attendance at existing self-management support services appears suboptimal despite their increased risk of developing many of the most serious long term conditions. The aim of this review was to determine whether current self-management support interventions are acceptable and accessible to men with long term conditions, and explore what may act as facilitators and barriers to access of interventions and support activities. Methods: A systematic search for qualitative research was undertaken on CINAHL, EMBASE, MEDLINE, PsycINFO and Social Science Citation Index, in July 2013. Reference lists of relevant articles were also examined. Studies that used a qualitative design to explore men’s experiences of, or perceptions towards, self-management support for one or more long term condition were included. Studies which focused on experiences of living with a long term condition without consideration of self-management support were excluded. Thirty-eight studies met the inclusion criteria. A meta-ethnography approach was employed to synthesise the findings. Results: Four constructs associated with men’s experience of, and perceptions towards, self management support were identified: 1) need for purpose; 2) trusted environments; 3) value of peers; and 4) becoming an expert. The synthesis showed that men may feel less comfortable participating in self-management support if it is viewed as incongruous with valued aspects of their identity, particularly when activities are perceived to challenge masculine ideals associated with independence, stoicism, and control. Men may find self-management support more attractive when it is perceived as action-oriented, having a clear purpose, and offering personally meaningful information and practical strategies that can be integrated into daily life. Conclusions: Self-management support is most likely to be successful in engaging men when it is congruent with key aspects of their masculine identity. In order to overcome barriers to access and fully engage with interventions, some men may need self-management support interventions to be delivered in an environment that offers a sense of shared understanding, connectedness, and normality, and involves and/or is facilitated by men with a shared illness experience

Poly(I:C) Enhances the Susceptibility of Leukemic Cells to NK Cell Cytotoxicity and Phagocytosis by DC

α Active specific immunotherapy aims at stimulating the host's immune system to recognize and eradicate malignant cells. The concomitant activation of dendritic cells (DC) and natural killer (NK) cells is an attractive modality for immune-based therapies. Inducing immunogenic cell death to facilitate tumor cell recognition and phagocytosis by neighbouring immune cells is of utmost importance for guiding the outcome of the immune response. We previously reported that acute myeloid leukemic (AML) cells in response to electroporation with the synthetic dsRNA analogue poly(I:C) exert improved immunogenicity, demonstrated by enhanced DC-activating and NK cell interferon-γ-inducing capacities. To further invigorate the potential of these immunogenic tumor cells, we explored their effect on the phagocytic and cytotoxic capacity of DC and NK cells, respectively. Using single-cell analysis, we assessed these functionalities in two- and three-party cocultures. Following poly(I:C) electroporation AML cells become highly susceptible to NK cell-mediated killing and phagocytosis by DC. Moreover, the enhanced killing and the improved uptake are strongly correlated. Interestingly, tumor cell killing, but not phagocytosis, is further enhanced in three-party cocultures provided that these tumor cells were upfront electroporated with poly(I:C). Altogether, poly(I:C)-electroporated AML cells potently activate DC and NK cell functions and stimulate NK-DC cross-talk in terms of tumor cell killing. These data strongly support the use of poly(I:C) as a cancer vaccine component, providing a way to overcome immune evasion by leukemic cells