Sustained home visiting for vulnerable families and children: a review of effective processes and strategies

Parenting young children has become a more complex and stressful business, especially for those families in our community with the least resources (Grose, 2006; Hayes et al, 2010; Poole, 2004; Richardson & Prior, 2005; Trask, 2010). A widening gap exists between families that function well and those that are vulnerable. The paradox of service delivery for children and families is that vulnerable families – that is, those families with the greatest needs – are also the least likely to be able to access those services (Ghate & Hazel, 2002; Fram, 2003). A range of barriers exist for vulnerable and at risk families in making use of services (Carbone et al, 2004). One of the key barriers to vulnerable families accessing services is that many find it difficult to relate to the formal service system and are easily alienated by practices others find acceptable. Research regarding parents’ experiences of support services suggests that parents want services where they are simultaneously cared for and enabled in their role as parents, and to receive services characterised by empathy, competence, functionality, respect, flexibility and honesty (Attride-Stirling et al, 2001; Winkworth et al, 2009). Vulnerable parents fear a loss of autonomy in their interactions with support services and want services that are non-judgemental and that provide continuity of care (Ghate & Hazel, 2002; von Bultzingslowen, 2006). In addition to the barriers faced by vulnerable and marginalised families in accessing services, the system does not work in an integrated or coherent fashion to ensure that all children and families needing support receive it. Furthermore, the vast majority of services for children and families in Australia do not have an outreach function, that is, a means of engaging these vulnerable and at risk families who are in need of support but use services inconsistently or not at all. In short, the service system was not designed to meet the needs of vulnerable families within the context of a rapidly changing social and economic climate. Therefore, many families requiring support are not receiving it. Related identifier: ISSN 2204-340

Historical cohort study examining comparative effectiveness of albuterol inhalers with and without integrated dose counter for patients with asthma or chronic obstructive pulmonary disease

This study was supported financially by an unrestricted grant from Teva Pharmaceuticals, Frazer, PA, USA. The authors thank Jenny Fanstone of Fanstone Medical Communications Ltd., UK, and Elizabeth V Hillyer for medical writing support, funded by Research in Real-Life. We acknowledge with gratitude Dr Ruchir Parikh for his review of and contributions to the manuscript.Peer reviewedPublisher PD

In vitro methods for Nrf2 pathway induction: Evaluation of the rotenone-induced activation of the Nrf2 pathway in a stem cell-derived neuronal model

Oxidative stress is one of the cellular responses determined at early stages of toxicity and can be induced by many different classes of chemicals. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) represents one of the key regulators of the Antioxidant-Response-Element-(ARE)-driven cellular defence mechanisms against oxidative stress. Nrf2 has been shown to have a cytoprotective, antioxidant and anti-inflammatory role in virtually all cell types in the body, both under physiological and disease conditions, as it regulates the expression of enzymes involved in detoxification processes. The SCR&Tox consortium, part of the SEURAT-1 research initiative, established to investigate Nrf2 signaling activation in neuronal models derived from hiPSCs. Analysis of Nrf2 signaling activation could serve as a base for the establishment of a horizontal assay to assess oxidative stress induction. Neuronal and glial cells undergo oxidative stress as an early response to different classes of chemicals, including inhibitors of mitochondrial respiration, such as rotenone, which is known to inhibit complex I of the mitochondrial respiratory chain. Moreover, human induced pluripotent stem cells (hiPSCs) are currently regarded as a powerful tool for drug and chemical screening and development of new in vitro testing strategies in the field of toxicology, including neurotoxicity and developmental neurotoxicity evaluation. This technical report summarizes the strategy adopted by EURL-ECVAM to assess Nrf2 signalling activation in neuronal models derived from hiPSCs. In particular, as agreed within the SCR&Tox consortium, two hiPSC-neuronal models were used: (i) an Nrf2-Luciferase reporter neural stem cell model (called Clone 27 (Cl27), obtained from Phenocell, France), and (ii) a wild type IMR90-hiPSC-derived neuronal/glial model (obtained from I-Stem, France). The results obtained with the wild type (IMR90-hiPSC) neuronal model indicate that rotenone induces the activation of Nrf2 signaling, increases the number of astroglial cells and decreases the number of dopaminergic neurons. The obtained results suggest that hiPSC-derived mixed neuronal/glial culture could be a valuable in vitro model for the establishment of neuronal specific assays to evaluate Nrf2 pathway activation (biomarker of oxidative stress) using neuronal specific readouts that could be applied to in vitro neurotoxicity evaluation.JRC.F.3-Chemicals Safety and Alternative Method

Hedgehog Signalling in Androgen Independent Prostate Cancer

Objectives: Androgen-deprivation therapy effectively shrinks hormone-naïve prostate cancer, both in the prostate and at sites of distant metastasis. However prolonged androgen deprivation generally results in relapse and androgen-independent tumour growth, which is inevitably fatal. The molecular events that enable prostate cancer cells to proliferate in reduced androgen conditions are poorly understood. Here we investigate the role of Hedgehog signalling in androgen-independent prostate cancer (AIPC). Methods: Activity of the Hedgehog signalling pathway was analysed in cultured prostate cancer cells, and circulating prostate tumour cells were isolated from blood samples of patients with AIPC. Results: AIPC cells were derived through prolonged culture in reduced androgen conditions, modelling hormone therapy in patients, and expressed increased levels of Hedgehog signalling proteins. Exposure of cultured AIPC cells to cyclopamine, which inhibits Hedgehog signalling, resulted in inhibition of cancer cell growth. The expression of the Hedgehog receptor PTCH and the highly prostate cancer-specific gene DD3PCA3 was significantly higher in circulating prostate cancer cells isolated from patients with AIPC compared with samples prepared from normal individuals. There was an association between PTCH and DD3PCA3 expression and the length of androgen-ablation therapy. Conclusions: Our data are consistent with reports implicating overactivity of Hedgehog signalling in prostate cancer and suggest that Hedgehog signalling contributes to the androgen-independent growth of prostate cancer cells. As systemic anti-Hedgehog medicines are developed, the Hedgehog pathway will become a potential new therapeutic target in advanced prostate cancer.Peer reviewedFinal Accepted Versio

Baseline and stress-induced levels of corticosterone in male and female Afrotropical and European temperate stonechats during breeding

Background: Latitudinal variation in avian life histories falls along a slow-fast pace of life continuum: tropical species produce small clutches, but have a high survival probability, while in temperate species the opposite pattern is found. This study investigated whether differential investment into reproduction and survival of tropical and temperate species is paralleled by differences in the secretion of the vertebrate hormone corticosterone (CORT). Depending on circulating concentrations, CORT can both act as a metabolic (low to medium levels) and a stress hormone (high levels) and, thereby, influence reproductive decisions. Baseline and stress-induced CORT was measured across sequential stages of the breeding season in males and females of closely related taxa of stonechats (Saxicola spp) from a wide distribution area. We compared stonechats from 13 sites, representing Canary Islands, European temperate and East African tropical areas. Stonechats are highly seasonal breeders at all these sites, but vary between tropical and temperate regions with regard to reproductive investment and presumably also survival. Results: In accordance with life-history theory, during parental stages, post-capture (baseline) CORT was overall lower in tropical than in temperate stonechats. However, during mating stages, tropical males had elevated post-capture (baseline) CORT concentrations, which did not differ from those of temperate males. Female and male mates of a pair showed correlated levels of post-capture CORT when sampled after simulated territorial intrusions. In contrast to the hypothesis that species with low reproduction and high annual survival should be more risk-sensitive, tropical stonechats had lower stress-induced CORT concentrations than temperate stonechats. We also found relatively high post-capture (baseline) and stress-induced CORT concentrations, in slow-paced Canary Islands stonechats. Conclusions: Our data support and refine the view that baseline CORT facilitates energetically demanding activities in males and females and reflects investment into reproduction. Low parental workload was associated with lower post-capture (baseline) CORT as expected for a slow pace of life in tropical species. On a finer resolution, however, this tropical-temperate contrast did not generally hold. Post-capture (baseline) CORT was higher during mating stages in particular in tropical males, possibly to support the energetic needs of mate-guarding. Counter to predictions based on life history theory, our data do not confirm the hypothesis that long-lived tropical populations have higher stress-induced CORT concentrations than short-lived temperate populations. Instead, in the predator-rich tropical environments of African stonechats, a dampened stress response during parental stages may increase survival probabilities of young. Overall our data further support an association between life history and baseline CORT, but challenge the role of stress-induced CORT as a mediator of tropical-temperate variation in life history

Changes in initial COPD treatment choice over time and factors influencing prescribing decisions in UK primary care : a real-world study

Acknowledgements Samantha Holmes (CircleScience, an Ashfield Company, part of UDG Healthcare plc) and Paul Hutchin (contracted to CircleScience, an Ashfield Company, part of UDG Healthcare plc) provided medical writing assistance. Funding The study was funded by Novartis Pharma AG (Basel, Switzerland).Peer reviewedPublisher PD

Hippocampal neuronal cells that accumulate α-synuclein fragments are more vulnerable to Aβ oligomer toxicity via mGluR5--implications for dementia with Lewy bodies.

BackgroundIn dementia with Lewy bodies (DLB) abnormal interactions between α-synuclein (α-syn) and beta amyloid (Aβ) result in selective degeneration of neurons in the neocortex, limbic system and striatum. However, factors rendering these neurons selectively vulnerable have not been fully investigated. The metabotropic glutamate receptor 5 (mGluR5) has been shown to be up regulated in DLB and might play a role as a mediator of the neurotoxic effects of Aβ and α-syn in vulnerable neuronal populations. In this context, the main objective of the present study was to investigate the role of mGluR5 as a mediator of the neurotoxic effects of α-syn and Aβ in the hippocampus.ResultsWe generated double transgenic mice over-expressing amyloid precursor protein (APP) and α-syn under the mThy1 cassette and investigated the relationship between α-syn cleavage, Aβ, mGluR5 and neurodegeneration in the hippocampus. We found that compared to the single tg mice, the α-syn/APP tg mice displayed greater accumulation of α-syn and mGluR5 in the CA3 region of the hippocampus compared to the CA1 and other regions. This was accompanied by loss of CA3 (but not CA1) neurons in the single and α-syn/APP tg mice and greater loss of MAP 2 and synaptophysin in the CA3 in the α-syn/APP tg. mGluR5 gene transfer using a lentiviral vector into the hippocampus CA1 region resulted in greater α-syn accumulation and neurodegeneration in the single and α-syn/APP tg mice. In contrast, silencing mGluR5 with a lenti-shRNA protected neurons in the CA3 region of tg mice. In vitro, greater toxicity was observed in primary hippocampal neuronal cultures treated with Aβ oligomers and over-expressing α-syn; this effect was attenuated by down-regulating mGluR5 with an shRNA lentiviral vector. In α-syn-expressing neuronal cells lines, Aβ oligomers promoted increased intracellular calcium levels, calpain activation and α-syn cleavage resulting in caspase-3-dependent cell death. Treatment with pharmacological mGluR5 inhibitors such as 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) attenuated the toxic effects of Aβ in α-syn-expressing neuronal cells.ConclusionsTogether, these results support the possibility that vulnerability of hippocampal neurons to α-syn and Aβ might be mediated via mGluR5. Moreover, therapeutical interventions targeting mGluR5 might have a role in DLB

Impact of phonon scattering in Si/GaAs/InGaAs nanowires and FinFets: a NEGF perspective

This paper reviews our previous theoretical studies and gives further insight into phonon scattering in 3D small nanotransistors using non-equilibrium Green function methodology. The focus is on very small gate-all-around nanowires with Si, GaAs or InGaAs cores. We have calculated phonon-limited mobility and transfer characteristics for a variety of cross-sections at low and high drain bias. The nanowire cross-sectional area is shown to have a significant impact on the phonon-limited mobility and on the current reduction. In a study of narrow Si nanowires we have examined the spatially resolved power dissipation and the validity of Joule’s law. Our results show that only a fraction of the power is dissipated inside the drain region even for a relatively large simulated length extension (approximately 30 nm). When considering large source regions in the simulation domain, at low gate bias, a slight cooling of the source is observed. We have also studied the impact of the real part of phonon scattering self-energy on a narrow nanowire transistor. This real part is usually neglected in nanotransistor simulation, whereas we compute its impact on current–voltage characteristic and mobility. At low gate bias, the imaginary part strongly underestimated the current and the mobility by 50 %. At high gate bias, the two mobilities are similar and the effect on the current is negligible

Strategic aims for improving the regulatory assessment of Developmental Neurotoxicity (DNT) using non-animal methods

Currently, the identification of chemicals that have the potential to induce developmental neurotoxicity (DNT) is based on animal testing, since there are no regulatory accepted alternative methods for this purpose. Since at the regulatory level, systematic testing of DNT is not a standard requirement within the EU legislation of chemical safety assessment, DNT testing is only performed in higher tiered tests triggered based on structure activity relationships or evidence of neurotoxicity in systemic adult studies. However, these triggers are rarely used and in addition do not always serve as reliable indicators of DNT as they are observed in an adult rodent animal. Consequently, to date only a limited amount of chemicals (Grandjean and Landrigan, 2006; Smirnova et al., 2014), mainly pesticides (Bjørling-Poulsen et al., 2008) have been tested under US EPA (OPPTS 870.630) or OECD DNT TG 426. Therefore, there is the pressing need for developing alternative methodologies that can more rapidly and cost-effectively screen large numbers of chemicals for their potential to cause DNT. In this report we propose that in vitro studies could contribute to the identification of potential triggers for DNT evaluation since existing cellular models permit the evaluation of a chemical impact on key neurodevelopmental processes, mimicking different windows of human brain development, especially if human models derived from induced pluripotent stem cells are applied. Furthermore, the battery of currently available DNT alternative test methods anchored to critical neurodevelopmental processes and key events identified in DNT Adverse Outcome Pathways (AOPs) could be applied to generate in vitro data useful for various regulatory purposes. Incorporation of in vitro mechanistic information would increase scientific confidence in decision making, by decreasing uncertainty and leading to refinement of chemical grouping according to biological activity. In this report development of IATA (Integrated Approaches to Testing and Assessment) based on key neurodevelopmental processes and AOP-informed is proposed as a tool for not only speeding up chemical screening, but also providing mechanistic data in support of hazard assessment and in the evaluation of chemical mixtures. Such mechanistically informed IATA for DNT evaluation could be developed integrating various sources of information (e.g., non-testing methods, in vitro approaches, as well as in vivo animal and human data), contributing to screening for prioritization, hazard identification and characterization, and possibly safety assessment of chemicals, speeding up the evaluation of thousands of compounds present in industrial, agricultural and consumer products that lack safety data on DNT potential. It is planned that the data and knowledge generated from such testing will be fed into the development of an OECD guidance document on alternative approaches to DNT testing.JRC.F.3-Chemicals Safety and Alternative Method

Archeota, Spring 2019

This is the Spring 2019 issue of Archeota, the official publication of SJSU SAASC. Archeota is a platform for students to contribute to the archival conversation. It is written BY students, FOR students. It provides substantive content on archival concerns and issues, and promotes career development in the field of archival studies. Archeota upholds the core values of the archival profession. It is a semiannual publication of the Student Chapter of the Society of American Archivists at the San Jose State University School of Information.https://scholarworks.sjsu.edu/saasc_archeota/1009/thumbnail.jp