Abstract-Atherosclerosis is an inflammatory disease occurring preferentially in arterial regions exposed to disturbed flow conditions including oscillatory shear stress (OS). OS exposure induces endothelial expression of bone morphogenic protein 4 (BMP4), which in turn may activate intercellular adhesion molecule-1 (ICAM-1) expression and monocyte adhesion. OS is also known to induce monocyte adhesion by producing reactive oxygen species (ROS) from reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, raising the possibility that BMP4 may stimulate the inflammatory response by ROS-dependent mechanisms. Here we show that ROS scavengers blocked ICAM-1 expression and monocyte adhesion induced by BMP4 or OS in endothelial cells (ECs). Similar to OS, BMP4 stimulated H 2 O 2 and O 2 Ϫ production in ECs. Next, we used ECs obtained from p47phox Ϫ/Ϫ mice (MAE-p47 Ϫ/Ϫ ), which do not produce ROS in response to OS, to determine the role of NADPH oxidases. Similar to OS, BMP4 failed to induce monocyte adhesion in MAE-p47 Ϫ/Ϫ , but it was restored when the cells were transfected with p47 phox plasmid. Moreover, OS-induced O 2 Ϫ production was blocked by noggin (a BMP antagonist), suggesting a role for BMP. Furthermore, OS increased gp91phox (nox2) and nox1 mRNA levels while decreasing nox4. In contrast, BMP4 induced nox1 mRNA expression, whereas nox2 and nox4 were decreased or not affected, respectively. Also, OS-induced monocyte adhesion was blocked by knocking down nox1 with the small interfering RNA (siRNA). Finally, BMP4 siRNA inhibited OS-induced ROS production and monocyte adhesion. Together, these results suggest that BMP4 produced in ECs by OS stimulates ROS release from the nox1-dependent NADPH oxidase leading to inflammation, a critical early atherogenic step. Key words: BMP4 Ⅲ oscillatory shear Ⅲ reactive oxygen species Ⅲ monocyte adhesion Ⅲ endothelial cells Ⅲ NADPH oxidase V ascular endothelial cells (ECs) are constantly exposed to fluid shear stress, the frictional force generated by blood flow over the vascular endothelium. The importance of shear stress in vascular biology and pathophysiology has been highlighted by the focal development patterns of atherosclerosis in hemodynamically defined regions. For example, the regions of branched and curved arteries exposed to disturbed flow conditions including oscillatory shear stress (OS) correspond to "lesion-prone areas" that preferentially develop atherosclerosis. 1,2 In contrast, straight arteries exposed to steady, high levels of laminar shear stress (LS) are relatively well protected from atherosclerotic plaque development. 1,2 Atherosclerosis is an inflammatory disease preferentially occurring in lesion-prone areas. 2,3 The earliest measurable markers of atherogenesis include expression of inflammatory adhesion molecules such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), and subsequent monocyte adhesion and recruitment into the lesion-prone areas. 2,4,5 Additional critical atherogen...

The redox potential of the plasma cysteine/cystine couple (E h CySS) is oxidized in association with risk factors for cardiovascular disease (CVD), including age, smoking, type 2 diabetes, obesity, and alcohol abuse. Previous in vitro findings support a cause-effect relationship for extracellular E h CySS in cell signaling pathways associated with CVD, including those controlling monocyte adhesion to endothelial cells. In this study, we provide evidence that mitochondria are a major source of reactive oxygen species (ROS) in the signaling response to a more oxidized extracellular E h CySS. This increase in ROS was blocked by overexpression of mitochondrial thioredoxin-2 (Trx2) in endothelial cells from Trx2-transgenic mice, suggesting that mitochondrial thiol antioxidant status plays a key role in this redox signaling mechanism. Mass spectrometry-based redox proteomics showed that several classes of plasma membrane and cytoskeletal proteins involved in inflammation responded to this redox switch, including vascular cell adhesion molecule, integrins, actin, and several Ras family GTPases. Together, the data show that the proinflammatory effects of oxidized plasma E h CySS are due to a mitochondrial signaling pathway that is mediated through redox control of downstream effector proteins.

5 Boroughs Partnership NHS Foundation Trust, in the Northwest of England, has trained over 500 staff in the Knowledge and Understanding Framework, level 1 personality disorder awareness training. This is a 3-day nationally devised training programme delivered via an innovative co-production model (i.e. co-delivery and partnership working with service users who have lived experience). This paper provides quantitative and qualitative information on the effectiveness of training delivery and also serves to provide some insight into the impact of service-user involvement via such a co-production model. Information on 162 participants using the Knowledge and Understanding Framework bespoke questionnaire (Personality Disorder Knowledge, Attitudes and Skills Questionnaire) suggests that the training can be effectively delivered by and within a local NHS Mental Health Trust. Results immediately post-training suggest an improvement in levels of understanding and capability efficacy and a reduction in negative emotional reactions. Indications from a 3-month follow-up suggest that while understanding and emotional reaction remain improved, capability efficacy regresses back to pre-training levels, suggesting the need for ongoing supervision and/or support to consolidate skills. Discussion includes guidelines for the implementation of a truly integrated co-production model of training provision, as well as advice relating to the maximization of long-term benefits.

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Background-Recent in vitro studies have shown that disturbed flow and oxidative conditions induce the expression of bone morphogenic proteins (BMPs 2 and 4) in cultured endothelial cells. BMPs can stimulate superoxide production and inflammatory responses in endothelial cells, raising the possibility that BMPs may play a role in vascular diseases such as hypertension and atherosclerosis. In this study, we examined the hypothesis that BMP4 would induce hypertension in intact animals by increasing superoxide production from vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and an impairment of vasodilation responses. Methods and Results-BMP4 infusion by osmotic pumps increased systolic blood pressure in a time-and dose-dependent manner in both C57BL/6 mice (from 101 to 125 mm Hg) and apolipoprotein E-null mice (from 107 to 146 mm Hg) after 4 weeks. Cotreatment with the BMP antagonist noggin or the NADPH oxidase inhibitor apocynin completely blocked the BMP4 effect. In addition, BMP4 infusion stimulated aortic NADPH oxidase activity and impaired vasorelaxation, both of which were prevented either by coinfusing noggin or by treating the isolated aortas with apocynin. BMP4, however, did not cause significant changes in maximum relaxation induced by the endothelium-independent vasodilator nitroglycerin. Remarkably, BMP4 infusion failed to stimulate aortic NADPH oxidases, increase blood pressure, and impair vasodilation responses in p47phox-deficient mice. Conclusions-These results suggest that BMP4 infusion induces hypertension in mice in a vascular NADPH oxidasedependent manner and the subsequent endothelial dysfunction. We suggest that BMP4 is a novel mediator of endothelial dysfunction and hypertension and that noggin and its analogs could be used as therapeutic agents for treating vascular diseases. (Circulation. 2006;113:2818-2825.)

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Evaluating the impact of a nationally recognised training programme that aims to raise the awareness and challenge attitudes of personality disorder in multi-agency partners.

This paper reports on a funded project that explored the perceptions and experiences of mentors regarding student nurse support in practice. The study employed a mixed-method approach, using questionnaires and focus groups with mentors from one acute Trust and one community Trust. The findings highlighted the multifaceted nature of student learning in practice, with mentors reporting that clinical skills, adjustment to the placement and integrating into the team were the aspects students needed most support with. Mentors were aware of their roles and responsibilities in supporting students and recognized the importance of their own personal attributes. The participants reported a number of challenges, particularly time, competing demands and paperwork, and suggested that a team approach and support groups could help to overcome these. The support for students provided by peers and health-care assistants was recognized, as was the need to ensure that students are prepared to take responsibility for their learning.