False Dawns and New Horizons in Patient Safety Research and Practice

In response to a weight of evidence that patients are frequently harmed as a result of their care, there have been concerted efforts to make healthcare safer, with health systems across the globe investing significant resources in policies and programmes designed to reduce adverse events. Yet, despite extensive efforts, improvements in safety have proved difficult to sustain and spread, with studies confirming there has been no measurable, systemslevel improvement in the overall rates of preventable harm. Here, we highlight the limitations of the thinking which underpins current efforts to make healthcare systems safer and point to new and emerging approaches to understanding and addressing patient safety in complex, dynamic health systems

Madness decolonized?: Madness as transnational identity in Gail Hornstein’s Agnes’s Jacket

The US psychologist Gail Hornstein’s monograph Agnes’s Jacket: A Psychologist’s Search for the Meanings of Madness (2009) is an important intervention in the identity politics of the mad movement. Hornstein offers a resignified vision of mad identity that embroiders the central trope of an “anti-colonial” struggle to reclaim the experiential world “colonized” by psychiatry. A series of literal and figurative appeals make recourse to the inner world and (corresponding) cultural world of the mad, as well as to the ethno-symbolic cultural materials of dormant nationhood. This rhetoric is augmented by a model in which the mad comprise a diaspora without an origin, coalescing into a single transnational community. The mad are also depicted as persons displaced from their metaphorical homeland, the “inner” world “colonized” by the psychiatric regime. There are a number of difficulties with Hornstein’s rhetoric, however. Her “ethnicity-and-rights” response to the oppression of the mad is symptomatic of Western parochialism, while her proposed transmutation of putative psychopathology from limit upon identity to parameter of successful identity is open to contestation. Moreover, unless one accepts Hornstein’s porous vision of mad identity, her self-ascribed insider status in relation to the mad community may present a problematic “re-colonization” of mad experience

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

Control of Dendritic Morphogenesis by Trio in Drosophila melanogaster

Abl tyrosine kinase and its effectors among the Rho family of GTPases each act to control dendritic morphogenesis in Drosophila. It has not been established, however, which of the many GTPase regulators in the cell link these signaling molecules in the dendrite. In axons, the bifunctional guanine exchange factor, Trio, is an essential link between the Abl tyrosine kinase signaling pathway and Rho GTPases, particularly Rac, allowing these systems to act coordinately to control actin organization. In dendritic morphogenesis, however, Abl and Rac have contrary rather than reinforcing effects, raising the question of whether Trio is involved, and if so, whether it acts through Rac, Rho or both. We now find that Trio is expressed in sensory neurons of the Drosophila embryo and regulates their dendritic arborization. trio mutants display a reduction in dendritic branching and increase in average branch length, whereas over-expression of trio has the opposite effect. We further show that it is the Rac GEF domain of Trio, and not its Rho GEF domain that is primarily responsible for the dendritic function of Trio. Thus, Trio shapes the complexity of dendritic arbors and does so in a way that mimics the effects of its target, Rac

Circulating and PBMC Lp-PLA2 Associate Differently with Oxidative Stress and Subclinical Inflammation in Nonobese Women (Menopausal Status)

BACKGROUND: This study aimed to determine the association of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity in circulation and peripheral blood mononuclear cells (PBMCs) with inflammatory and oxidative stress markers in nonobese women and according to menopausal status. Lp-PLA(2) activity, a marker for cardiovascular risk is associated with inflammation and oxidative stress. METHODOLOGY/PRINCIPAL FINDINGS: Eighty postmenopausal women (53.0±4.05 yr) and 96 premenopausal women (39.7±9.25 yr) participated in this study. Lp-PLA(2) activities, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β in plasma as well as in PBMCs were measured. Plasma ox-LDL was also measured. Postmenopausal women demonstrated higher circulating levels of ox-LDL and IL-6, as well as IL-6, TNF-α, and IL-1β in PBMCs, than premenopausal women. In both groups, plasma Lp-PLA(2) activity positively correlated with Lp-PLA(2) activity in PBMCs and plasma ox-LDL. In premenopausal women, Lp-PLA(2) activities in plasma and PBMCs positively correlated with IL-6, TNF-α, and IL-1β in PBMCs. In postmenopausal women, plasma ox-LDL positively correlated with PBMC cytokine production. In subgroup analysis of postmenopausal women according to plasma ox-LDL level (median level: 48.715 U/L), a significant increase in Lp-PLA(2) activity in the plasma but not the PBMCs was found in the high ox-LDL subgroup. Plasma Lp-PLA(2) activity positively correlated with unstimulated PBMC Lp-PLA(2) activity in the low ox-LDL subgroup (r = 0.627, P<0.001), whereas in the high ox-LDL circulating Lp-PLA(2) activity positively correlated with plasma ox-LDL (r = 0.390, P = 0.014) but not with Lp-PLA(2) activity in PBMCs. CONCLUSIONS/SIGNIFICANCE: The lack of relation between circulating Lp-PLA(2) activity and Lp-PLA(2) activity in PBMCs was found in postmenopausal women with high ox-LDL. This may indicate other sources of circulating Lp-PLA(2) activity except PBMC in postmenopausal women with high ox-LDL. We also demonstrated that circulating Lp-PLA(2) and PBMC secreted Lp-PLA(2) associate differently with markers of oxidative stress and sub clinical inflammation in nonobese women, particularly according to the menopausal states

Positional Cues in the Drosophila Nerve Cord: Semaphorins Pattern the Dorso-Ventral Axis

Positional cues target sensory axons to appropriate volumes of the developing nervous system independently of their synaptic partners

Genetic variation and exercise-induced muscle damage: implications for athletic performance, injury and ageing.

Prolonged unaccustomed exercise involving muscle lengthening (eccentric) actions can result in ultrastructural muscle disruption, impaired excitation-contraction coupling, inflammation and muscle protein degradation. This process is associated with delayed onset muscle soreness and is referred to as exercise-induced muscle damage. Although a certain amount of muscle damage may be necessary for adaptation to occur, excessive damage or inadequate recovery from exercise-induced muscle damage can increase injury risk, particularly in older individuals, who experience more damage and require longer to recover from muscle damaging exercise than younger adults. Furthermore, it is apparent that inter-individual variation exists in the response to exercise-induced muscle damage, and there is evidence that genetic variability may play a key role. Although this area of research is in its infancy, certain gene variations, or polymorphisms have been associated with exercise-induced muscle damage (i.e. individuals with certain genotypes experience greater muscle damage, and require longer recovery, following strenuous exercise). These polymorphisms include ACTN3 (R577X, rs1815739), TNF (-308 G>A, rs1800629), IL6 (-174 G>C, rs1800795), and IGF2 (ApaI, 17200 G>A, rs680). Knowing how someone is likely to respond to a particular type of exercise could help coaches/practitioners individualise the exercise training of their athletes/patients, thus maximising recovery and adaptation, while reducing overload-associated injury risk. The purpose of this review is to provide a critical analysis of the literature concerning gene polymorphisms associated with exercise-induced muscle damage, both in young and older individuals, and to highlight the potential mechanisms underpinning these associations, thus providing a better understanding of exercise-induced muscle damage

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference