Hypoxia in atherogenesis

The anoxemia theory proposes that an imbalance between the demand for and supply of oxygen in the arterial wall is a key factor in the development of atherosclerosis. There is now substantial evidence that there are regions within the atherosclerotic plaque in which profound hypoxia exists; this may fundamentally change the function, metabolism, and responses of many of the cell types found within the developing plaque and whether the plaque will evolve into a stable or unstable phenotype. Hypoxia is characterized in molecular terms by the stabilization of hypoxia-inducible factor (HIF) 1a, a subunit of the heterodimeric nuclear transcriptional factor HIF-1 and a master regulator of oxygen homeostasis. The expression of HIF-1 is localized to perivascular tissues, inflammatory macrophages, and smooth muscle cells adjacent to the necrotic core of atherosclerotic lesions and regulates several genes that are important to vascular function including vascular endothelial growth factor, nitric oxide synthase, endothelin-1, and erythropoietin. This review summarizes the effects of hypoxia on the functions of cells involved in atherogenesis and the evidence for its potential importance from experimental models and clinical studies

Low oxygen tension primes aortic endothelial cells to the reparative effect of tissue-protective cytokines

Erythropoietin (EPO) has both erythropoietic and tissue-protective properties. The EPO analogues carbamylated EPO (CEPO) and pyroglutamate helix B surface peptide (pHBSP) lack the erythropoietic activity of EPO but retain the tissue-protective properties that are mediated by a heterocomplex of EPO receptor (EPOR) and the β common receptor (βCR). We studied the action of EPO and its analogues in a model of wound healing where a bovine aortic endothelial cells (BAECs) monolayer was scratched and the scratch closure was assessed over 24 h under different oxygen concentrations. We related the effects of EPO and its analogues on repair to their effect on BAECs proliferation and migration (evaluated using a micro-Boyden chamber). EPO, CEPO and pHBSP enhanced scratch closure only at lower oxygen (5%), while their effect at atmospheric oxygen (21%) was not significant. The mRNA expression of EPOR was doubled in 5% compared to 21% oxygen, and this was associated with increased EPOR assessed by immunofluorescence and Western blot. By contrast βCR mRNA levels were similar in 5% and 21% oxygen. EPO and its analogues increased both BAECs proliferation and migration, suggesting that both may be involved in the reparative process. The priming effect of low oxygen tension on the action of tissue-protective cytokines may be of relevance to vascular disease, including atherogenesis and restenosis

Recruitment, retention, and training of people with type 2 diabetes as diabetes prevention mentors (DPM) to support a healthcare professional-delivered diabetes prevention program:The Norfolk Diabetes Prevention Study (NDPS)

Objective: Intensive lifestyle interventions reduce the risk of type 2 diabetes in populations at highest risk, but staffing levels are usually unable to meet the challenge of delivering effective prevention strategies to a very large at-risk population. Training volunteers with existing type 2 diabetes to support healthcare professionals deliver lifestyle interventions is an attractive option. Methods: We identified 141 973 people at highest risk of diabetes in the East of England, screened 12 778, and randomized 1764 into a suite of type 2 diabetes prevention and screen detected type 2 diabetes management trials. A key element of the program tested the value of volunteers with type 2 diabetes, trained to act as diabetes prevention mentors (DPM) when added to an intervention arm delivered by healthcare professionals trained to support participant lifestyle change. Results: We invited 9951 people with type 2 diabetes to become DPM and 427 responded (4.3%). Of these, 356 (83.3%) were interviewed by phone, and of these 131 (36.8%) were interviewed in person. We then appointed 104 of these 131 interviewed applicants (79%) to the role (mean age 62 years, 55% (n=57) male). All DPMs volunteered for a total of 2895 months, and made 6879 telephone calls to 461 randomized participants. Seventy-six (73%) DPMs volunteered for at least 6 months and 66 (73%) for at least 1 year. Discussion: Individuals with type 2 diabetes can be recruited, trained and retained as DPM in large numbers to support a group-based diabetes prevention program delivered by healthcare professionals. This volunteer model is low cost, and accesses the large type 2 diabetes population that shares a lifestyle experience with the target population. This is an attractive model for supporting diabetes prevention efforts

Long-term MRA follow-up after coiling of intracranial aneurysms: impact on mood and anxiety

Magnetic resonance angiography (MRA) screening for recurrence of a coiled intracranial aneurysm and formation of new aneurysms long-term after coiling may induce anxiety and depression. In coiled patients, we evaluated effects on mood and level of anxiety from long-term follow-up MRA in comparison to general population norms. Of 162 patients participating in a long-term (> 4.5 years) MRA follow-up after coiling, 120 completed the EQ-5D questionnaire, a visual analog health scale and a self-developed screening related questionnaire at the time of MRA. Three months later, the same questionnaires were completed by 100 of these 120 patients. Results were compared to general population norms adjusted for gender and age. Any problem with anxiety or depression was reported in 56 of 120 patients (47%; 95%CI38a dagger"56%) at baseline and 42 of 100 patients (42%; 95%CI32a dagger"52%) at 3 months, equally for screen-positives and -negatives. Compared to the reference population, participants scored 38% (95%CI9a dagger"67%) and 27% (95%CI4a dagger"50%) more often any problem with anxiety or depression. Three months after screening, 21% (20 of 92) of screen-negatives and 13% (one of eight) of screen-positives reported to be less afraid of subarachnoid hemorrhage (SAH) compared to before screening. One of eight screen-positives reported increased fear of SAH. Patients with coiled intracranial aneurysms participating in long-term MRA screening reported significantly more often to be anxious or depressed than a reference group. Screening did not significantly increase anxiety or depression temporarily. However, subjectively, patients did report an increase in anxiety caused by screening, which decreased after 3 months

Management of Hypertriglyceridemia in the Diabetic Patient

The hypertriglyceridemia of diabetes can be classified into mild to moderate (triglycerides between 150–499 mg/dL) and severe hypertriglyceridemia (triglycerides ≥500 mg/dL). As in any other individuals with hypertriglyceridemia, secondary causes need to be excluded. The management of severe hypertriglyceridemia (chylomicronemia syndrome) includes aggressive reduction of triglycerides with intravenous insulin, fibrates, omega-3 fatty acids, and/or niacin therapy to avert the risk of pancreatitis. In patients with mild to moderate hypertriglyceridemia, the treatment of choice is statin therapy to achieve the low-density lipoprotein (LDL) and non-high-density lipoprotein (HDL) target goals. The evidence base would favor niacin therapy in combination with statin therapy to achieve the goals pertaining to LDL cholesterol and non-HDL cholesterol. The data about the combination of fibrate therapy with statin therapy are disappointing

Simultaneous intra/extravascular administration of antiproliferative agents as a new strategy to inhibit restenosis: The peak of reactive cell proliferation as a hallmark for the duration of the treatment

BACKGROUND: Strictly intravascular approaches for the treatment of postangioplasty restenosis are effective in the intima and the inner parts of the media but may be insufficient to control redundant pathways in the more outer parts of the media and the adventitia. An inverse situation may occur subsequently to a strictly extravascular approach, like the recently suggested pericardial approach in pigs. We hypothesized that simultaneous intra/extravascular administration of anti-restenotic agents inhibits restenosis by blocking all stimulatory pathways in the entire arterial wall. METHODS: Fresh hearts of 25 domestic pigs were obtained from a local slaughterhouse. Left anterior descending coronary arteries (LAD) were harvested, cut into cylindric 5 mm segments, and cultured as ex vivo porcine organ cultures (POCs). After 9 bar ballooning simultaneous intra/extravascular administration of high dose diltiazem (50 μg/mL) was carried out for a period of 1, 2, 3, 4, 5, 6, and 7 days. At day 7 and 28 proliferative activity (BrdU), neointimal thickening, and staining against smooth muscle α-actin and vWF was analysed. RESULTS: 7 days after ballooning administration of diltiazem for 4, 5, 6, and 7 days inhibited reactive cell proliferation by more than 50% (n.s.) as compared to control, 28 days after ballooning administration for 6 and 7 days inhibited neointimal thickening by more than 75% (p < 0.05). Simultaneous intra/extravascular administration of high dose diltiazem did not affect the expression of vWF in endothelial cells or smooth muscle α-actin in smooth muscle cells. CONCLUSIONS: Simultaneous intra/extravascular administration of high dose diltiazem (50 μg/mL) has to be maintained for at least 6 days to achieve a significant inhibition of neointimal thickening. The data demonstrate the importance of the maximal reactive cell proliferation (= day 7 in the POC-model) for the calculation of the duration of the treatment period

Workplace violence in a large correctional health servce in New South Wales, Australia: a retrospective review of incident management records

BackgroundLittle is known about workplace violence among correctional health professionals. This studyaimed to describe the patterns, severity and outcomes of incidents of workplace violenceamong employees of a large correctional health service, and to explore the help-seekingbehaviours of staff following an incident.MethodsThe study setting was Justice Health, a statutory health corporation established to providehealth care to people who come into contact with the criminal justice system in New SouthWales, Australia. We reviewed incident management records describing workplace violenceamong Justice Health staff. The three-year study period was 1/7/2007-30/6/2010.ResultsDuring the period under review, 208 incidents of workplace violence were recorded. Verbalabuse (71%) was more common than physical abuse (29%). The most (44%) incidents ofworkplace violence (including both verbal and physical abuse) occurred in adult maleprisons, although the most (50%) incidents of physical abuse occurred in a forensic hospital.Most (90%) of the victims were nurses and two-thirds were females. Younger employees andmales were most likely to be a victim of physical abuse. Preparing or dispensing medicationand attempting to calm and/or restrain an aggressive patient were identified as ‘high risk’work duties for verbal abuse and physical abuse, respectively. Most (93%) of the incidents ofworkplace violence were initiated by a prisoner/patient. Almost all of the incidents receivedeither a medium (46%) or low (52%) Severity Assessment Code. Few victims of workplaceviolence incurred a serious physical injury – there were no workplace deaths during the studyperiod. However, mental stress was common, especially among the victims of verbal abuse(85%). Few (6%) victims of verbal abuse sought help from a health professional.ConclusionsAmong employees of a large correctional health service, verbal abuse in the workplace wassubstantially more common than physical abuse. The most incidents of workplace violenceoccurred in adult male prisons. Review of the types of adverse health outcomes experiencedby the victims of workplace violence and the assessments of severity assigned to violentincidents suggests that, compared with health care settings in the community, correctionalsettings are fairly safe places in which to practice

Over-Expression of PDGFR-β Promotes PDGF-Induced Proliferation, Migration, and Angiogenesis of EPCs through PI3K/Akt Signaling Pathway

The proliferation, migration, and angiogenesis of endothelial progenitor cells (EPCs) play critical roles in postnatal neovascularization and re-endothelialization following vascular injury. Here we evaluated whether the over-expression of platelet-derived growth factor receptor-β (PDGFR-β) can enhance the PDGF-BB-stimulated biological functions of EPCs through the PDGFR-β/phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. We first confirmed the expression of endogenous PDGFR-β and its plasma membrane localization in spleen-derived EPCs. We then demonstrated that the PDGFR-β over-expression in EPCs enhanced the PDGF-BB-induced proliferation, migration, and angiogenesis of EPCs. Using AG1295 (a PDGFR kinase inhibitor), LY294002 (a PI3K inhibitor), and sc-221226 (an Akt inhibitor), we further showed that the PI3K/Akt signaling pathway participates in the PDGF-BB-induced proliferation, migration, and angiogenesis of EPCs. In addition, the PI3K/Akt signaling pathway is required for PDGFR-β over-expression to enhance these PDGF-BB-induced phenotypes

Effect of a Dipeptidyl Peptidase-IV Inhibitor, Des-Fluoro-Sitagliptin, on Neointimal Formation after Balloon Injury in Rats

Background: Recently, it has been suggested that enhancement of incretin effect improves cardiac function. We investigated the effect of a DPP-IV inhibitor, des-fluoro-sitagliptin, in reducing occurrence of restenosis in carotid artery in response to balloon injury and the related mechanisms. Methods and Findings: Otsuka Long-Evans Tokushima Fatty rats were grouped into four: control (normal saline) and sitagliptin 100, 250 and 500 mg/kg per day (n = 10 per group). Sitagliptin or normal saline were given orally from 1 week before to 2 weeks after carotid injury. After 3 weeks of treatment, sitagliptin treatment caused a significant and dose-dependent reduction in intima-media ratio (IMR) in obese diabetic rats. This effect was accompanied by improved glucose homeostasis, decreased circulating levels of high-sensitivity C-reactive protein (hsCRP) and increased adiponectin level. Moreover, decreased IMR was correlated significantly with reduced hsCRP, tumor necrosis factor-$\alpha$ and monocyte chemoattractant protein-1 levels and plasminogen activator inhibitor-1 activity. In vitro evidence with vascular smooth muscle cells (VSMCs) demonstrated that proliferation and migration were decreased significantly after sitagliptin treatment. In addition, sitagliptin increased caspase-3 activity and decreased monocyte adhesion and NFκB activation in VSMCs. Conclusions: Sitagliptin has protective properties against restenosis after carotid injury and therapeutic implications for treating macrovascular complications of diabetes