Interaction of Stress, Lead Burden, and Age on Cognition in Older Men: The VA Normative Aging Study

BACKGROUND. Low-level exposure to lead and to chronic stress may independently influence cognition. However, the modifying potential of psychosocial stress on the neurotoxicity of lead and their combined relationship to aging-associated decline have not been fully examined. OBJECTIVES. We examined the cross-sectional interaction between stress and lead exposure on Mini-Mental State Examination (MMSE) scores among 811 participants in the Normative Aging Study, a cohort of older U.S. men. METHODS. We used two self-reported measures of stress appraisal-a self-report of stress related to their most severe problem and the Perceived Stress Scale (PSS). Indices of lead exposure were blood lead and bone (tibia and patella) lead. RESULTS. Participants with higher self-reported stress had lower MMSE scores, which were adjusted for age, education, computer experience, English as a first language, smoking, and alcohol intake. In multivariable-adjusted tests for interaction, those with higher PSS scores had a 0.57-point lower (95% confidence interval, -0.90 to 0.24) MMSE score for a 2-fold increase in blood lead than did those with lower PSS scores. In addition, the combination of high PSS scores and high blood lead categories on one or both was associated with a 0.05-0.08 reduction on the MMSE for each year of age compared with those with low PSS score and blood lead level (p < 0.05). CONCLUSIONS. Psychological stress had an independent inverse association with cognition and also modified the relationship between lead exposure and cognitive performance among older men. Furthermore, high stress and lead together modified the association between age and cognition.National Institutes of Health (R01ES07821, R01HL080674, R01HL080674-02S1, R01ES013744, ES05257-06A1, P20MD000501, P42ES05947, ES03918-02); National Center for Research Resources General Clinical Research Center (M01RR02635); Leaves of Grass Foundation; United States Department of Veterans Affair

Remarkable Progress with Small-Molecule Modulation of TRPC1/4/5 Channels: Implications for Understanding the Channels in Health and Disease

Proteins of the TRPC family can form many homo- and heterotetrameric cation channels permeable to Na+, K+ and Ca2+. In this review, we focus on channels formed by the isoforms TRPC1, TRPC4 and TRPC5. We review evidence for the formation of different TRPC1/4/5 tetramers, give an overview of recently developed small-molecule TRPC1/4/5 activators and inhibitors, highlight examples of biological roles of TRPC1/4/5 channels in different tissues and pathologies, and discuss how high-quality chemical probes of TRPC1/4/5 modulators can be used to understand the involvement of TRPC1/4/5 channels in physiological and pathophysiological processes

Pregnancy glycaemia and cord-blood levels of insulin and leptin in Pakistani and white British mother–offspring pairs: findings from a prospective pregnancy cohort

Aims/hypothesis To determine the extent to which gestational fasting and postload levels of glucose explain differences in infant fat mass between UK-born Pakistani and white British infants. Methods Analyses were undertaken in a prospective pregnancy cohort study of 1,415 women and their singleton live-born infants (629 white British and 786 Pakistani). Infant fat mass was assessed by cord-blood leptin levels and fetal insulin secretion by cord-blood insulin levels. Maternal OGTTs were completed at 26–28 weeks of gestation. Results Pakistani women had higher fasting and postload glucose levels and greater incidence of gestational diabetes than white British women. Higher fasting and postload glucose levels were associated with higher cord-blood levels of insulin and leptin in all participants, irrespective of ethnicity. Cord-blood leptin levels were 16% (95% CI 6, 26) higher in Pakistani than in white British infants. After adjustment for fasting glucose levels, this difference attenuated to 7% (−3, 16), and with additional adjustment for cord-blood insulin levels it attenuated further to 5% (−4, 14). Path analyses supported the hypothesis that fasting glucose levels mediate the relationship of Pakistani ethnicity to greater fat mass at birth, as measured by cord-blood leptin levels; on average, 19% of this mediation involved fetal insulin secretion. Postload glucose levels did not act as an important mediator of ethnic differences in cord-blood leptin levels. Results were very similar when 130 women with gestational diabetes were removed. Conclusions/interpretation These novel findings suggest a role of maternal pregnancy glycaemia in mediating differences in fat mass between Pakistani and white British infants

PCV13 induced IgG responses in serum associate with serotype-specific IgG in the lung

Pneumococcal conjugate vaccine efficacy is lower for non-invasive pneumonia than invasive disease. In this study, participants were vaccinated with PCV13 or HepA (control). Bronchoalveolar lavage samples were taken between 2-6 months and serum at 4- and 7-weeks post vaccination. In the lung, anti-capsular IgG levels were higher in the PCV13 group compared to control for all serotypes, except 3 and 6B. Systemically, IgG levels were elevated in the PCV group at 4-weeks for all serotypes, except 3. IgG in BAL and serum positively correlated for nearly all serotypes. PCV13 shows poor immunogenicity to serotype 3, implying lack of protective efficacy. Clinical trial registration with ISRCTN: 4534043

Current undergraduate dental implantology teaching in UK

Dental Implants are a popular treatment option for tooth replacement, with documented long-term success and survival rates of more than 95% over a period of 10 years. However, incorporating dental implantology into an undergraduate dental curriculum has issues associated. Therefore, the aim of this research was to examine and evaluate current undergraduate dental implantology education in the UK, investigate the amount of time allocated to this subject and analyse the barriers that are currently impeding the development of the programmes. An online questionnaire hosted by Online Surveys was designed, piloted, and sent to 16 dental schools providing undergraduate education in the UK. Ethical approval was gained from The University of Salford to conduct the study. Out of the 16 dental schools contacted, eight questionnaire responses were received, hence a response rate of 50% was achieved. The hours dedicated to the implant teaching programme varied from 3 h to 25 h, with a mean average of 11 h. It was identified from the results that no teaching of dental implantology was conducted in year 2; 12% of the schools responded that the subject was taught in year 1, 37% in year 3, 75% in year 4 and 50% in year 5. The methods used to deliver the programme were mainly lecture-based teaching, with only one dental school allowing students to place implants on patients. The main barriers to progression of the programme were financial (75%), followed by time limitations imposed by the curriculum (37%) and liability insurance (37%). However, there appears to be a consensus that further training beyond bachelor's degree level is required to teach implantology effectively.</b

Antigenic Complementarity in the Origins of Autoimmunity: A General Theory Illustrated With a Case Study of Idiopathic Thrombocytopenia Purpura

We describe a novel, testable theory of autoimmunity, outline novel predictions made by the theory, and illustrate its application to unravelling the possible causes of idiopathic thrombocytopenia purpura (ITP). Pairs of stereochemically complementary antigens induce complementary immune responses (antibody or T-cell) that create loss of regulation and civil war within the immune system itself. Antibodies attack antibodies creating circulating immune complexes; T-cells attack T-cells creating perivascular cuffing. This immunological civil war abrogates the self-nonself distinction. If at least one of the complementary antigens mimics a self antigen, then this unregulated immune response will target host tissues as well. Data demonstrating that complementary antigens are found in some animal models of autoimmunity and may be present in various human diseases, especially ITP, are reviewed. Specific mechanisms for preventing autoimmunity or suppressing existing autoimmunity are derived from the theory, and critical tests proposed. Finally, we argue that Koch's postulates are inadequate for establishing disease causation for multiple-antigen diseases and discuss the possibility that current research has failed to elucidate the causes of human autoimmune diseases because we are using the wrong criteria

Human TRPC5 structures reveal interaction of a xanthine-based TRPC1/4/5 inhibitor with a conserved lipid binding site

TRPC1/4/5 channels are non-specific cation channels implicated in a wide variety of diseases, and TRPC1/4/5 inhibitors have recently entered clinical trials. However, fundamental and translational studies require a better understanding of TRPC1/4/5 channel regulation by endogenous and exogenous factors. Although several potent and selective TRPC1/4/5 modulators have been reported, the paucity of mechanistic insights into their modes-of-action remains a barrier to the development of new chemical probes and drug candidates. Xanthine-based modulators include the most potent and selective TRPC1/4/5 inhibitors described to date, as well as TRPC5 activators. Our previous studies suggest that xanthines interact with a, so far, elusive pocket of TRPC1/4/5 channels that is essential to channel gating. Here we report the structure of a small-molecule-bound TRPC1/4/5 channel—human TRPC5 in complex with the xanthine Pico145—to 3.0 Å. We found that Pico145 binds to a conserved lipid binding site of TRPC5, where it displaces a bound phospholipid. Our findings explain the mode-of-action of xanthine-based TRPC1/4/5 modulators, and suggest a structural basis for TRPC1/4/5 modulation by endogenous factors such as (phospho)lipids and Zn2+ ions. These studies lay the foundations for the structure-based design of new generations of TRPC1/4/5 modulators

Can we continue research in splenectomized dogs? Mycoplasma haemocanis: Old problem - New insight

We report the appearance of a Mycoplasma haemocanis infection in laboratory dogs, which has been reported previously, yet, never before in Europe. Outbreak of the disease was triggered by a splenectomy intended to prepare the dogs for a hemorrhagic shock study. The clinical course of the dogs was dramatic including anorexia and hemolytic anemia. Treatment included allogeneic transfusion, prednisone, and oxytetracycline. Systematic follow-up (n=12, blood smears, antibody testing and specific polymerase chain reaction) gives clear evidence that persistent eradication of M. haemocanis is unlikely. We, therefore, had to abandon the intended shock study. In the absence of effective surveillance and screening for M. haemocanis, the question arises whether it is prudent to continue shock research in splenectomized dogs. Copyright (C) 2004 S. Karger AG, Basel

Scale, history and justice in community wind energy: An empirical review

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordAlthough there is a clear positive link between community wind energy (CWE) projects and social acceptance, there is still empirical and conceptual ambiguity concerning the details of why. To fill this gap, we revisit foundational papers in this field and then, focusing on empirical case studies between 2010 and 2018 (n = 15), trace how recent research has engaged with existing conceptual frameworks. Most empirical researchers verify the importance of the two key dimensions defined by Walker & Devine-Wright [1]: process and outcome, and then relate this to procedural justice and distributive justice. Meanwhile, the core concept of “community” has been deployed, in both practice and research, in so many different and sometimes ambiguous ways that it remains difficult to assert if, and how, community-based renewable energy policy and siting practice produces high levels of local community acceptance. We suggest that parsing out the scale of investment in wind energy projects and the local historical context of energy transitions add clarity to the Walker & Devine-Wright framework as it relates to CWE; providing important conceptual nuance for guiding policy, developer practices and future empirical research.Social Sciences and Humanities Research Council of Canad

The IBER study: a feasibility randomised controlled trial of imagery based emotion regulation for the treatment of anxiety in bipolar disorder

BACKGROUND: Intrusive mental imagery is associated with anxiety and mood instability within bipolar disorder and therefore represents a novel treatment target. Imagery Based Emotion Regulation (IBER) is a brief structured psychological intervention developed to enable people to use the skills required to regulate the emotional impact of these images. METHODS: Participants aged 18 and over with a diagnosis of bipolar disorder and at least a mild level of anxiety were randomly assigned (1:1) to receive IBER plus treatment as usual (IBER + TAU) or treatment as usual alone (TAU). IBER was delivered in up to 12 sessions overs 16 weeks. Clinical and health economic data were collected at baseline, end of treatment and 16-weeks follow-up. Objectives were to inform the recruitment process, timeline and sample size estimate for a definitive trial and to refine trial procedures. We also explored the impact on participant outcomes of anxiety, depression, mania, and mood stability at 16-weeks and 32-weeks follow-up. RESULTS: Fifty-seven (28: IBER + TAU, 27: TAU) participants from two sites were randomised, with 50 being recruited within the first 12 months. Forty-seven (82%) participants provided outcome data at 16 and 32-weeks follow-up. Thirty-five participants engaged in daily mood monitoring at the 32-week follow-up stage. Retention in IBER treatment was high with 27 (96%) attending ≥ 7 sessions. No study participants experienced a serious adverse event. DISCUSSION: The feasibility criteria of recruitment, outcome completion, and intervention retention were broadly achieved, indicating that imagery-focused interventions for bipolar disorder are worthy of further investigation