Elevated 4R-tau in astrocytes from asymptomatic carriers of the MAPT 10+16 intronic mutation

The microtubule-associated protein tau gene (MAPT) 10+16 intronic mutation causes frontotemporal lobar degeneration (FTLD) by increasing expression of four-repeat (4R)-tau isoforms. We investigated the potential role for astrocytes in the pathogenesis of FTLD by studying the expression of 4R-tau. We derived astrocytes and neurons from induced pluripotent stem cells from two asymptomatic 10+16 carriers which, compared to controls, showed persistently increased 4R:3R-tau transcript and protein ratios in both cell types. However, beyond 300 days culture, 10+16 neurons showed less marked increase of this 4R:3R-tau transcript ratio compared to astrocytes. Interestingly, throughout maturation, both 10+16 carriers consistently displayed different 4R:3R-tau transcript and protein ratios. These elevated levels of 4R-tau in astrocytes implicate glial cells in the pathogenic process and also suggests a cell-type-specific regulation and may inform and help on treatment of pre-clinical tauopathies

Sexual behaviour of men that consulted in medical outpatient clinics in Western Switzerland from 2005-2006: risk levels unknown to doctors?

<p>Abstract</p> <p>Background</p> <p>To determine male outpatient attenders' sexual behaviours, expectations and experience of talking about their sexuality and sexual health needs with a doctor.</p> <p>Methods</p> <p>A survey was conducted among all male patients aged 18-70, recruited from the two main medical outpatient clinics in Lausanne, Switzerland, in 2005-2006. The anonymous self-administered questionnaire included questions on sexual behaviour, HIV/STI information needs, expectations and experiences regarding discussion of sexual matters with a doctor.</p> <p>Results</p> <p>The response rate was 53.0% (N = 1452). The mean age was 37.7 years. Overall, 13.4% of patients were defined as at STI risk - i.e. having not consistently used condoms with casual partners in the last 6 months, or with a paid partner during the last intercourse - regarding their sexual behaviour in the last year. 90.9% would have liked their physician to ask them questions concerning their sexual life; only 61.4% had ever had such a discussion. The multivariate analysis showed that patients at risk tended to have the following characteristics: recruited from the HIV testing clinic, lived alone, declared no religion, had a low level of education, felt uninformed about HIV/AIDS, were younger, had had concurrent sexual partners in the last 12 months. However they were not more likely to have discussed sexual matters with their doctor than patients not at risk.</p> <p>Conclusion</p> <p>Recording the sexual history and advice on the prevention of the risks of STI should become routine practice for primary health care doctors.</p

Human induced pluripotent stem cell-derived microglia-like cells harboring TREM2 missense mutations show specific deficits in phagocytosis

Dysfunction of microglia, the brain’s immune cells, is linked to neurodegeneration. Homozygous missense mutations in TREM2 cause Nasu-Hakola disease (NHD), an early-onset dementia. To study the consequences of these TREM2 variants, we generated induced pluripotent stem cell-derived microglia-like cells (iPSC-MGLCs) from patients with NHD caused by homozygous T66M or W50C missense mutations. iPSC-MGLCs expressed microglial markers and secreted higher levels of TREM2 than primary macrophages. TREM2 expression and secretion were reduced in variant lines. LPS-mediated cytokine secretion was comparable between control and TREM2 variant iPSC-MGLCs, whereas survival was markedly reduced in cells harboring missense mutations when compared with controls. Furthermore, TREM2 missense mutations caused a marked impairment in the phagocytosis of apoptotic bodies, but not in Escherichia coli or zymosan substrates. Coupled with changes in apoptotic cell-induced cytokine release and migration, these data identify specific deficits in the ability of iPSC-MGLCs harboring TREM2 missense mutations to respond to specific pathogenic signals

iPSC-derived neuronal models of PANK2-associated neurodegeneration reveal mitochondrial dysfunction contributing to early disease

Mutations in PANK2 lead to neurodegeneration with brain iron accumulation. PANK2 has a role in the biosynthesis of coenzyme A (CoA) from dietary vitamin B5, but the neuropathological mechanism and reasons for iron accumulation remain unknown. In this study, atypical patient-derived fibroblasts were reprogrammed into induced pluripotent stem cells (iPSCs) and subsequently differentiated into cortical neuronal cells for studying disease mechanisms in human neurons. We observed no changes in PANK2 expression between control and patient cells, but a reduction in protein levels was apparent in patient cells. CoA homeostasis and cellular iron handling were normal, mitochondrial function was affected; displaying activated NADH-related and inhibited FADH-related respiration, resulting in increased mitochondrial membrane potential. This led to increased reactive oxygen species generation and lipid peroxidation in patient-derived neurons. These data suggest that mitochondrial deficiency is an early feature of the disease process and can be explained by altered NADH/FADH substrate supply to oxidative phosphorylation. Intriguingly, iron chelation appeared to exacerbate the mitochondrial phenotype in both control and patient neuronal cells. This raises caution for the use iron chelation therapy in general when iron accumulation is absent

An evaluation of gender equity in different models of primary care practices in Ontario

Background: The World Health Organization calls for more work evaluating the effect of health care reforms on gender equity in developed countries. We performed this evaluation in Ontario, Canada where primary care models resulting from reforms co-exist. // Methods: This cross sectional study of primary care practices uses data collected in 2005-2006. Healthcare service models included in the study consist of fee for service (FFS) based, salaried, and capitation based. We compared the quality of care delivered to women and men in practices of each model. We performed multi-level, multivariate regressions adjusting for patient socio-demographic and economic factors to evaluate vertical equity, and adjusting for these and health factors in evaluating horizontal equity. We measured seven dimensions of health service delivery (e.g. accessibility and continuity) and three dimensions of quality of care using patient surveys (n = 5,361) and chart abstractions (n = 4,108). // Results: Health service delivery measures were comparable in women and men, with differences ≤ 2.2% in all seven dimensions and in all models. Significant gender differences in the health promotion subjects addressed were observed. Female specific preventive manoeuvres were more likely to be performed than other preventive care. Men attending FFS practices were more likely to receive influenza immunization than women (Adjusted odds ratio: 1.75, 95% confidence intervals (CI) 1.05, 2.92). There was no difference in the other three prevention indicators. FFS practices were also more likely to provide recommended care for chronic diseases to men than women (Adjusted difference of -11.2%, CI -21.7, -0.8). A similar trend was observed in Community Health Centers (CHC). // Conclusions: The observed differences in the type of health promotion subjects discussed are likely an appropriate response to the differential healthcare needs between genders. Chronic disease care is non equitable in FFS but not in capitation based models. We recommend that efforts to monitor and address gender based differences in the delivery of chronic disease management in primary care be pursued.Funding for the original study on which this research is based was provided by the Ontario Ministry of Health and Long Term Care Primary Health Care Transition Fund. The views expressed in this report are the views of the authors and do not necessarily reflect those of the Ontario Ministry of Health and Long Term Care

Time spent on work-related activities, social activities and time pressure as intermediary determinants of health disparities among elderly women and men in 5 European countries: a structural equation model

Background Psychosocial factors shape the health of older adults through complex inter-relating pathways. Besides socioeconomic factors, time use activities may explain gender inequality in self-reported health. This study investigated the role of work-related and social time use activities as determinants of health in old age. Specifically, we analysed whether the impact of stress in terms of time pressure on health mediated the relationship between work-related time use activities (i.e. housework and paid work) on self-reported health. Methods We applied structural equation models and a maximum-likelihood function to estimate the direct and indirect effects of psychosocial factors on health using pooled data from the Multinational Time Use Study on 11,168 men and 14,295 women aged 65+ from Italy, Spain, UK, France and the Netherlands. Results The fit indices for the conceptual model indicated an acceptable fit for both men and women. The results showed that socioeconomic status (SES), demographic factors, stress and work-related time use activities after retirement had a significant direct influence on self-reported health among the elderly, but the magnitude of the effects varied by gender. Social activities had a positive impact on self-reported health but had no significant impact on stress among older men and women. The indirect standardized effects of work-related activities on self-reported health was statistically significant for housework (β = − 0.006; P  0.05 among women), which implied that the paths from paid work and housework on self-reported health via stress (mediator) was very weak because their indirect effects were close to zero. Conclusions Our findings suggest that although stress in terms of time pressure has a direct negative effect on health, it does not indirectly influence the positive effects of work-related time use activities on self-reported health among elderly men and women. The results support the time availability hypothesis that the elderly may not have the same time pressure as younger adults after retirement

Socioeconomic status and health in the second half of life: findings from the German Ageing Survey

This study examined social inequalities in health in the second half of life. Data for empirical analyses came from the second wave of the German Ageing Survey (DEAS), an ongoing population-based, representative study of community dwelling persons living in Germany, aged 40–85 years (N = 2,787). Three different indicators for socioeconomic status (SES; education, income, financial assets as an indicator for wealth) and health (physical, functional and subjective health) were employed. It could be shown that SES was related to health in the second half of life: Less advantaged persons between 40 and 85 years of age had worse health than more advantaged persons. Age gradients varied between status indicators and health dimensions, but in general social inequalities in health were rather stable or increasing over age. The latter was observed for wealth-related absolute inequalities in physical and functional health. Only income-related differences in subjective health decreased at higher ages. The amount of social inequality in health as well as its development over age did not vary by gender and place of residence (East or West Germany). These results suggest that, in Germany, the influence of SES on health remains important throughout the second half of life

Proneoplastic effects of PGE2 mediated by EP4 receptor in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Prostaglandin E₂(PGE₂) is the major product of Cyclooxygenase-2 (COX-2) in colorectal cancer (CRC). We aimed to assess PGE₂cell surface receptors (EP 1–4) to examine the mechanisms by which PGE₂regulates tumour progression.</p> <p>Methods</p> <p>Gene expression studies were performed by quantitative RT-PCR. Cell cycle was analysed by flow cytometry with cell proliferation quantified by BrdU incorporation measured by enzyme immunoassay. Immunohistochemistry was employed for expression studies on formalin fixed paraffin embedded tumour tissue.</p> <p>Results</p> <p>EP4 was the most abundant subtype of PGE₂receptor in HT-29 and HCA7 cells (which show COX-2 dependent PGE₂generation) and was consistently the most abundant transcript in human colorectal tumours (n = 8) by qRT-PCR (ANOVA, p = 0.01). G0/G1 cell cycle arrest was observed in HT-29 cells treated with SC-236 5 μM (selective COX-2 inhibitor) for 24 hours (p = 0.02), an effect abrogated by co-incubation with PGE₂(1 μM). G0/G1 arrest was also seen with a specific EP4 receptor antagonist (EP4A, L-161982) (p = 0.01). Treatment of HT-29 cells with either SC-236 or EP4A caused reduction in intracellular cAMP (ANOVA, p = 0.01). Early induction in p21^WAF1/CIP1expression (by qRT-PCR) was seen with EP4A treatment (mean fold increase 4.4, p = 0.04) while other genes remained unchanged. Similar induction in p21^WAF1/CIP1was also seen with PD153025 (1 μM), an EGFR tyrosine kinase inhibitor, suggesting EGFR transactivation by EP4 as a potential mechanism. Additive inhibition of HCA7 proliferation was observed with the combination of SC-236 and neutralising antibody to amphiregulin (AR), a soluble EGFR ligand. Concordance in COX-2 and AR localisation in human colorectal tumours was noted.</p> <p>Conclusion</p> <p>COX-2 regulates cell cycle transition via EP4 receptor and altered p21^WAF1/CIP1expression. EGFR pathways appear important. Specific targeting of the EP4 receptor or downstream targets may offer a safer alternative to COX-2 inhibition in the chemoprevention of CRC.</p

The role of prostaglandin E2 (PGE 2) in toll-like receptor 4 (TLR4)-mediated colitis-associated neoplasia

<p>Abstract</p> <p>Background</p> <p>We have previously found that TLR4-deficient (TLR4-/-) mice demonstrate decreased expression of mucosal PGE ₂and are protected against colitis-associated neoplasia. However, it is still unclear whether PGE ₂is the central factor downstream of TLR4 signaling that promotes intestinal tumorigenesis. To further elucidate critical downstream pathways involving TLR4-mediated intestinal tumorigenesis, we examined the effects of exogenously administered PGE ₂in TLR4-/- mice to see if PGE ₂bypasses the protection from colitis-associated tumorigenesis.</p> <p>Method</p> <p>Mouse colitis-associated neoplasia was induced by azoxymethane (AOM) injection followed by two cycles of dextran sodium sulfate (DSS) treatment. Two different doses of PGE ₂(high dose group, 200 μg, n = 8; and low dose group, 100 μg, n = 6) were administered daily during recovery period of colitis by gavage feeding. Another group was given PGE ₂during DSS treatment (200 μg, n = 5). Inflammation and dysplasia were assessed histologically. Mucosal Cox-2 and amphiregulin (AR) expression, prostanoid synthesis, and EGFR activation were analyzed.</p> <p>Results</p> <p>In control mice treated with PBS, the average number of tumors was greater in WT mice (n = 13) than in TLR4-/- mice (n = 7). High dose but not low dose PGE ₂treatment caused an increase in epithelial proliferation. 28.6% of PBS-treated TLR4-/- mice developed dysplasia (tumors/animal: 0.4 ± 0.2). By contrast, 75.0% (tumors/animal: 1.5 ± 1.2, P < 0.05) of the high dose group and 33.3% (tumors/animal: 0.3 ± 0.5) of the low dose group developed dysplasia in TLR4-/- mice. Tumor size was also increased by high dose PGE ₂treatment. Endogenous prostanoid synthesis was differentially affected by PGE ₂treatment during acute and recovery phases of colitis. Exogenous administration of PGE ₂increased colitis-associated tumorigenesis but this only occurred during the recovery phase. Lastly, PGE ₂treatment increased mucosal expression of AR and Cox-2, thus inducing EGFR activation and forming a positive feedback mechanism to amplify mucosal Cox-2.</p> <p>Conclusions</p> <p>These results highlight the importance of PGE ₂as a central downstream molecule involving TLR4-mediated intestinal tumorigenesis.</p