Synthesis and characterisation of novel ru(II) complexes with selective deuteriation

The aim of my research was to investigate Ru(II) mixed ligand complexes through synthesis and characterisation and through the use of deuteriation. The location of the excited state in the dinuclear species was to be determined through use of selective deuteriation of ligands. Acid/ base dependency o f these 1,2,4-triazolecontaining complexes may be applied in the area of supramolecular chemistry due to its switch on/off effect. However to arrive at this stage a series of studies were necessary. In chapter 3, reveals the description of the synthesis of the starting material [Ru(L)2Cl2].2H2O, where L is bipyridyl, phenanthroline and biquinoline. This is followed by the deuteriation of these ligands (bpy, phen and biq) and the Hpytr and Hpztr ligands. The starting materials with the deuteriated ligands dg-bpy, dg-phen and di2-biq where consequently prepared .The synthesis and characterisation of the ligands 3-(pyridin-2-yl)-l,2,4-triazole, Hpytr and 3-(pyrazin-2-yl)-l,2,4-triazole, Hpztr and their complexes are shown in chapter 3. The use of deuteriation in the location of the excited state of the pztr' complexes was not as facile as first thought as the complex was found to have dual emitting properties due to close-lying excited states. New developments arose in the isolation of the stereoisomers of the pytr' and pztr complexes in collaboration with Dr. C. Villani, University of Rome, also a new concept of 99R u NMR was investigated of the pytr' and pztr isomers in collaboration with Prof. C. Elsevier, University of Amsterdam. Chapter 4 is the investigation of complexes containing the ligand 3-(pyrazin-2-yl)-5- (pyridin-2-yl)-l,2,4-triazole, Hppt. This ligand was synthesised and also deuteriated to prepare selectively deuteriated complexes as in chapter 3 with the same starting materials. The synthesis and characterisation was described in this chapter for these complexes and y9Ru NMR was obtained. Also a crystal structure of the N2 of the triazole ring to the pyrazine isomer of the ppf complex was achieved. Chapter 5 is the conclusive chapter of this text, which describes the synthesis of the dinuclear complexes of the ppf ligand, and this is prepared via two routes the indirect and the direct route. The indirect route is prepared using the isolated isomers of the monomers. The characterisation and selective deuteriation is discussed. From the redox and photophysical behaviour of the dinuclear complexes some theories were derived. Chapter 6 is conclusions and future work, which sums up the results o f this thesis and the consequential studies, which have evolved

Testing mood-activated psychological markers for suicidal ideation

To what extent are death- and life-oriented psychological processes among suicidal individuals activated by mood? According to Teasdale’s (1988) Differential Activation Hypothesis, we would expect that negative mood-activated psychological processes are maladaptive among suicide ideators (vs. non-ideators) and predictive of subsequent suicidal ideation. This, however, has never been prospectively studied. To address this knowledge gap, we conducted a prospective study assessing psychological risk factors via the Death/Life Implicit Association Test (IAT) and the Suicide Stroop task before and after a temporary negative mood induction. Suicidal ideation was assessed one and six months later. Results based on Death/Life IAT performance largely supported hypotheses, such that suicide ideators demonstrated significantly weaker implicit identification with life after (vs. before) the negative mood induction. Non-ideators demonstrated no significant change, maintaining strong identification with life irrespective of mood. Of note, this baseline interaction may have been accounted for by depressive symptoms. Identification with death (vs. life) predicted greater likelihood of suicidal ideation one month later, controlling for depressive symptoms and baseline suicidal ideation. Only negative mood-activated identification with death predicted suicidal ideation six months later. Suicide Stroop scores did not change as a function of mood or predict subsequent suicidal ideation. Death/Life IAT findings support the Differential Activation Hypothesis and suggest that suicide ideators’ identification with life is more variable and easily weakened by negative mood relative to non-ideators. We encourage future work to consider the potential role of transient mood and the importance of measuring psychological processes that pertain to both death and life

Interferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus Latency.

Human cytomegalovirus (HCMV) latency is an active process which remodels the latently infected cell to optimize latent carriage and reactivation. This is achieved, in part, through the expression of viral genes, including the G-protein-coupled receptor US28. Here, we use an unbiased proteomic screen to assess changes in host proteins induced by US28, revealing that interferon-inducible genes are downregulated by US28. We validate that major histocompatibility complex (MHC) class II and two pyrin and HIN domain (PYHIN) proteins, myeloid cell nuclear differentiation antigen (MNDA) and IFI16, are downregulated during experimental latency in primary human CD14+ monocytes. We find that IFI16 is targeted rapidly during the establishment of latency in a US28-dependent manner but only in undifferentiated myeloid cells, a natural site of latent carriage. Finally, by overexpressing IFI16, we show that IFI16 can activate the viral major immediate early promoter and immediate early gene expression during latency via NF-κB, a function which explains why downregulation of IFI16 during latency is advantageous for the virus.IMPORTANCE Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus which infects 50 to 100% of humans worldwide. HCMV causes a lifelong subclinical infection in immunocompetent individuals but is a serious cause of mortality and morbidity in the immunocompromised and neonates. In particular, reactivation of HCMV in the transplant setting is a major cause of transplant failure and related disease. Therefore, a molecular understanding of HCMV latency and reactivation could provide insights into potential ways to target the latent viral reservoir in at-risk patient populations

Differences in IV alcohol-induced dopamine release in the ventral striatum of social drinkers and nontreatment-seeking alcoholics

Background Striatal dopamine (DA) has been implicated in alcohol use disorders, but it is still unclear whether or not alcohol can induce dopamine release in social drinkers. Furthermore, no data exist on dopamine responses to alcohol in dependent drinkers. We sought to characterize the DA responses to alcohol intoxication in moderately large samples of social drinkers (SD) and nontreatment-seeking alcoholics (NTS). Methods Twenty-four SD and twenty-one NTS received two [11C]raclopride (RAC) PET scans; one at rest, and one during an intravenous alcohol infusion, with a prescribed ascent to a target breath alcohol concentration (BrAC), at which it was then “clamped.” The alcohol clamp was started 5 min after scan start, with a linear increase in BrAC over 15 min to the target of 80 mg%, the legal threshold for intoxication. Target BrAC was maintained for 30 min. Voxel-wise binding potential (BPND) was estimated with MRTM2. Results IV EtOH induced significant increases in DA in the right ventral striatum in NTS, but not SD. No decreases in DA were observed in either group. Conclusions Alcohol intoxication results in distinct anatomic profiles of DA responses in SD and NTS, suggesting that in NTS, the striatal DA system may process effects of alcohol intoxication differently than in SD

Investigating the psychometric properties of the Suicide Stroop task

Behavioral measures are increasingly used to assess suicidal thoughts and behaviors. Some measures, such as the Suicide Stroop Task, have yielded mixed findings in the literature. An understudied feature of these behavioral measures has been their psychometric properties, which may affect the probability of detecting significant effects and reproducibility. In the largest investigation of its kind, we tested the internal consistency and concurrent validity of the Suicide Stroop Task in its current form, drawing from seven separate studies (N = 875 participants, 64% female, aged 12 to 81 years). Results indicated that the most common Suicide Stroop scoring approach, interference scores, yielded unacceptably low internal consistency (rs = -.09-.13) and failed to demonstrate concurrent validity. Internal consistency coefficients for mean reaction times (RTs) to each stimulus type ranged from rs = .93-.94. All scoring approaches for suicide-related interference demonstrated poor classification accuracy (AUCs = .52-.56) indicating that scores performed near chance in their ability to classify suicide attempters from nonattempters. In the case of mean RTs, we did not find evidence for concurrent validity despite our excellent reliability findings, highlighting that reliability does not guarantee a measure is clinically useful. These results are discussed in the context of the wider implications for testing and reporting psychometric properties of behavioral measures in mental health research

Decision aids for respite service choices by carers of people with dementia: development and pilot RCT

<p>Abstract</p> <p>Background</p> <p>Decision aids are often used to assist individuals confronted with a diagnosis of a serious illness to make decisions about treatment options. However, they are rarely utilised to help those with chronic or age related conditions to make decisions about care services. Decision aids should also be useful for carers of people with decreased decisional capacity. These carers' choices must balance health outcomes for themselves and for salient others with relational and value-based concerns, while relying on information from health professionals. This paper reports on a study that both developed and pilot tested a decision aid aimed at assisting carers to make evaluative judgements of community services, particularly respite care.</p> <p>Methods</p> <p>A mixed method sequential study, involving qualitative development and a pilot randomised controlled trial, was conducted in Tasmania, Australia. We undertook 13 semi-structured interviews and three focus groups to inform the development of the decision aid. For the randomised control trial we randomly assigned 31 carers of people with dementia to either receive the service decision aid at the start or end of the study. The primary outcome was measured by comparing the difference in carer burden between the two groups three months after the intervention group received the decision aid. Pilot data was collected from carers using interviewer-administered questionnaires at the commencement of the project, two weeks and 12 weeks later.</p> <p>Results</p> <p>The qualitative data strongly suggest that the intervention provides carers with needed decision support. Most carers felt that the decision aid was useful. The trial data demonstrated that, using the mean change between baseline and three month follow-up, the intervention group had less increase in burden, a decrease in decisional conflict and increased knowledge compared to control group participants.</p> <p>Conclusions</p> <p>While these results must be interpreted with caution due to the small sample size, all intervention results trend in a direction that is beneficial for carers and their decisional ability. Mixed method data suggest the decision aid provides decisional support that carers do not otherwise receive. Decision aids may prove useful in a community health services context.</p> <p>Trial registration number</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN32163031">ISRCTN32163031</a></p

The Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium: design, methods, and study population

Background: Single birth cohort studies have been the basis for many discoveries about early life risk factors for childhood asthma but are limited in scope by sample size and characteristics of the local environment and population. The Children’s Respiratory and Environmental Workgroup (CREW) was established to integrate multiple established asthma birth cohorts and to investigate asthma phenotypes and associated causal pathways (endotypes), focusing on how they are influenced by interactions between genetics, lifestyle, and environmental exposures during the prenatal period and early childhood. Methods and results: CREW is funded by the NIH Environmental influences on Child Health Outcomes (ECHO) program, and consists of 12 individual cohorts and three additional scientific centers. The CREW study population is diverse in terms of race, ethnicity, geographical distribution, and year of recruitment. We hypothesize that there are phenotypes in childhood asthma that differ based on clinical characteristics and underlying molecular mechanisms. Furthermore, we propose that asthma endotypes and their defining biomarkers can be identified based on personal and early life environmental risk factors. CREW has three phases: 1) to pool and harmonize existing data from each cohort, 2) to collect new data using standardized procedures, and 3) to enroll new families during the prenatal period to supplement and enrich extant data and enable unified systems approaches for identifying asthma phenotypes and endotypes. Conclusions: The overall goal of CREW program is to develop a better understanding of how early life environmental exposures and host factors interact to promote the development of specific asthma endotypes.HHS/NIH [5UG3OD023282]; Columbia University [P01ES09600, R01 ES008977, P30ES09089, R01 ES013163, R827027]; Tucson Children's Respiratory Study (TCRS) [NHLBI 132523]; Infant Immune Study (IIS) [HL-56177]; Childhood Origins of Asthma Study (COAST) [P01 HL070831, U10 HL064305, R01 HL061879]; Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) [R01 AI050681, R56 AI050681, R01 AI061774, R21 AI059415, K01 AI070606, R21 AI069271, R01 HL113010, R21 ES022321, P01 AI089473, R21 AI080066, R01 AI110450, R01 HD082147]; Fund for Henry Ford Health System; Childhood Allergy Study (CAS) [R01 AI024156, R03 HL067427, R01 AI051598]; Blue Cross Foundation Johnson; Fund for Henry Ford Hospital; Microbes, Allergy, Asthma and Pets (MAAP) [P01 AI089473]; Infant Susceptibility to Pulmonary Infections and Asthma following RSV Exposure (INSPIRE) [NIH/NIAID U19 AI 095227, NIH/NCATS UL1 TR 002243, NIH/NIAID K24 AI 077930, NIH/NHLBI R21 HD 087864, NIH/NHLBI X01 HL 134583]; Wisconsin Infant Study Cohort (WISC) [U19 AI104317, NCATS UL1TR000427]; Upper Midwest Agricultural Safety and Health Center (UMASH) [U54 OH010170]; RTI International, Research Triangle Park, North Carolina, USA; NIH [U24OD023382]; Urban Environment and Childhood Asthma Study (URECA) [NO1-AI-25482, HHSN272200900052C, HHSN272201000052I, NCRR/NIH RR00052, M01RR00533, 1UL1RR025771, M01RR00071, 1UL1RR024156, UL1TR001079, 5UL1RR024992-02, NCATS/NIH UL1TR000040]; Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) [R01 ES11170, R01 ES019890]; Epidemiology of Home Allergens and Asthma Study (EHAAS) [R01 AI035786]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Protocol for a randomised controlled trial of a decision aid for the management of pain in labour and childbirth [ISRCTN52287533]

BACKGROUND: Women report fear of pain in childbirth and often lack complete information on analgesic options prior to labour. Preferences for pain relief should be discussed before labour begins. A woman's antepartum decision to use pain relief is likely influenced by her cultural background, friends, family, the media, literature and her antenatal caregivers. Pregnant women report that information about analgesia was most commonly derived from hearsay and least commonly from health professionals. Decision aids are emerging as a promising tool to assist practitioners and their patients in evidence-based decision making. Decision aids are designed to assist patients and their doctors in making informed decisions using information that is unbiased and based on high quality research evidence. Decision aids are non-directive in the sense that they do not aim to steer the user towards any one option, but rather to support decision making which is informed and consistent with personal values. METHODS/DESIGN: We aim to evaluate the effectiveness of a Pain Relief for Labour decision aid, with and without an audio-component, compared to a pamphlet in a three-arm randomised controlled trial. Approximately 600 women expecting their first baby and planning a vaginal birth will be recruited for the trial. The primary outcomes of the study are decisional conflict (uncertainty about a course of action), knowledge, anxiety and satisfaction with decision-making and will be assessed using self-administered questionnaires. The decision aid is not intended to influence the type of analgesia used during labour, however we will monitor health service utilisation rates and maternal and perinatal outcomes. This study is funded by a competitive peer-reviewed grant from the Australian National Health and Medical Research Council (No. 253635). DISCUSSION: The Pain Relief for Labour decision aid was developed using the Ottawa Decision Support Framework and systematic reviews of the evidence about the benefits and risks of the non-pharmacological and pharmacological methods of pain relief for labour. It comprises a workbook and worksheet and has been developed in two forms – with and without an audio-component (compact disc). The format allows women to take the decision aid home and discuss it with their partner

Maternal antibiotic administration during a critical developmental window has enduring neurobehavioural effects in offspring mice

Rates of perinatal maternal antibiotic use have increased in recent years linked to prophylactic antibiotic use following Caesarean section delivery. This antibiotic use is necessary and beneficial in the short-term; however, long-term consequences on brain and behaviour have not been studied in detail. Here, we endeavoured to determine whether maternal administration of antibiotics during a critical window of development in early life has lasting effects on brain and behaviour in offspring mice. To this end we studied two different antibiotic preparations (single administration of Phenoxymethylpenicillin at 31 mg/kg/day; and a cocktail consisting of, ampicillin 1 mg/mL; vancomycin 0.5 mg/mL; metronidazole 1 mg/mL; ciprofloxacin 0.2 mg/mL and imipenem 0.25 mg/mL). It was observed that early life exposure to maternal antibiotics led to persistent alterations in anxiety, sociability and cognitive behaviours. These effects in general were greater in animals treated with the broad-spectrum antibiotic cocktail compared to a single antibiotic with the exception of deficits in social recognition which were more robustly observed in Penicillin V exposed animals. Given the prevalence of maternal antibiotic use, our findings have potentially significant translational relevance, particularly considering the implications on infant health during this critical period and into later life

Clouds, aerosols, and precipitation in the marine boundary layer: an ARM Mobile Facility Deployment

The Clouds, Aerosol, and Precipitation in the Marine Boundary Layer (CAP-MBL) deployment at Graciosa Island in the Azores generated a 21-month (April 2009–December 2010) comprehensive dataset documenting clouds, aerosols, and precipitation using the Atmospheric Radiation Measurement Program (ARM) Mobile Facility (AMF). The scientific aim of the deployment is to gain improved understanding of the interactions of clouds, aerosols, and precipitation in the marine boundary layer. Graciosa Island straddles the boundary between the subtropics and midlatitudes in the northeast Atlantic Ocean and consequently experiences a great diversity of meteorological and cloudiness conditions. Low clouds are the dominant cloud type, with stratocumulus and cumulus occurring regularly. Approximately half of all clouds contained precipitation detectable as radar echoes below the cloud base. Radar and satellite observations show that clouds with tops from 1 to 11 km contribute more or less equally to surface-measured precipitation at Graciosa. A wide range of aerosol conditions was sampled during the deployment consistent with the diversity of sources as indicated by back-trajectory analysis. Preliminary findings suggest important two-way interactions between aerosols and clouds at Graciosa, with aerosols affecting light precipitation and cloud radiative properties while being controlled in part by precipitation scavenging. The data from Graciosa are being compared with short-range forecasts made with a variety of models. A pilot analysis with two climate and two weather forecast models shows that they reproduce the observed time-varying vertical structure of lower-tropospheric cloud fairly well but the cloud-nucleating aerosol concentrations less well. The Graciosa site has been chosen to be a permanent fixed ARM site that became operational in October 2013