Effect of ramipril on walking times and quality of life among patients with peripheral artery disease and intermittent claudication : a randomized controlled trial

Importance Approximately one-third of patients with peripheral artery disease experience intermittent claudication, with consequent loss of quality of life. Objective To determine the efficacy of ramipril for improving walking ability, patient-perceived walking performance, and quality of life in patients with claudication. Design, Setting, and Patients Randomized, double-blind, placebo-controlled trial conducted among 212 patients with peripheral artery disease (mean age, 65.5 [SD, 6.2] years), initiated in May 2008 and completed in August 2011 and conducted at 3 hospitals in Australia. Intervention Patients were randomized to receive 10 mg/d of ramipril (n = 106) or matching placebo (n = 106) for 24 weeks. Main Outcome Measures Maximum and pain-free walking times were recorded during a standard treadmill test. The Walking Impairment Questionnaire (WIQ) and Short-Form 36 Health Survey (SF-36) were used to assess walking ability and quality of life, respectively. Results At 6 months, relative to placebo, ramipril was associated with a 75-second (95% CI, 60-89 seconds) increase in mean pain-free walking time (P < .001) and a 255-second (95% CI, 215-295 seconds) increase in maximum walking time (P < .001). Relative to placebo, ramipril improved the WIQ median distance score by 13.8 (Hodges-Lehmann 95% CI, 12.2-15.5), speed score by 13.3 (95% CI, 11.9-15.2), and stair climbing score by 25.2 (95% CI, 25.1-29.4) (P < .001 for all). The overall SF-36 median Physical Component Summary score improved by 8.2 (Hodges-Lehmann 95% CI, 3.6-11.4; P = .02) in the ramipril group relative to placebo. Ramipril did not affect the overall SF-36 median Mental Component Summary score. Conclusions and Relevance Among patients with intermittent claudication, 24-week treatment with ramipril resulted in significant increases in pain-free and maximum treadmill walking times compared with placebo. This was associated with a significant increase in the physical functioning component of the SF-36 score. Trial Registration clinicaltrials.gov Identifier: NCT00681226

Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes

Senescence and genomic integrity are thought to be important barriers in the development of malignant lesions. Human fibroblasts undergo a limited number of cell divisions before entering an irreversible arrest, called senescence. Here we show that human mammary epithelial cells (HMECs) do not conform to this paradigm of senescence. In contrast to fibroblasts, HMECs exhibit an initial growth phase that is followed by a transient growth plateau (termed selection or M0; refs 3-5), from which proliferative cells emerge to undergo further population doublings (approximately 20-70), before entering a second growth plateau (previously termed senescence or M1; refs 4-6). We find that the first growth plateau exhibits characteristics of senescence but is not an insurmountable barrier to further growth. HMECs emerge from senescence, exhibit eroding telomeric sequences and ultimately enter telomere-based crisis to generate the types of chromosomal abnormalities seen in the earliest lesions of breast cancer. Growth past senescent barriers may be a pivotal event in the earliest steps of carcinogenesis, providing many genetic changes that predicate oncogenic evolution. The differences between epithelial cells and fibroblasts provide new insights into the mechanistic basis of neoplastic transformation.

Loss of chromosomal integrity in human mammary epithelial cells subsequent to escape from senescence

The genomic changes that foster cancer can be either genetic or epigenetic in nature. Early studies focused on genetic changes and how mutational events contribute to changes in gene expression. These point mutations, deletions and amplifications are known to activate oncogenes and inactivate tumor suppressor genes. More recently, multiple epigenetic changes that can have a profound effect on carcinogenesis have been identified. These epigenetic events, such as the methylation of promoter sequences in genes, are under active investigation. In this review we will describe a methylation event that occurs during the propagation of human mammary epithelial cells (HMEC) in culture and detail the accompanying genetic alterations that have been observed.

Internal audit involvement in enterprise risk management

Purpose The paper examines the impact of internal auditors’ involvement in Enterprise Risk Management (ERM) on perceptions of their willingness to report a breakdown in risk procedures and whether a strong relationship with the audit committee affects such willingness to report. The study also investigates the use of ERM and the role of internal audit in ERM in Australian private and public sector entities. Design/methodology/approach The study uses an experimental design, manipulating (i) the internal auditor’s involvement in ERM and (ii) the strength of the relationship between internal audit and the audit committee. Participants are 117 certified internal auditors. The study also gathers descriptive data on the use of ERM. Findings The study indicates that a high involvement in ERM impacts the perceptions of internal auditors’ willingness to report a breakdown in risk procedures to the audit committee. However, a strong relationship with the audit committee does not appear to affect their perceived willingness to report. The study also finds that the majority of organisations have recently adopted ERM. Internal auditors are involved in ERM assurance activities but some also engage in activities that could compromise objectivity.

Optimising employee engagement with internal communication : a social exchange perspective

Drawing on principles of social exchange this thesis employs mediated regression to investigate the relationship between internal communication and employee engagement in the Australian workforce. Findings suggest organisations and supervisors should focus internal communication efforts toward building greater perceptions of support and stronger identification among employees in order to foster optimal engagement. This research contributes to public relations and management scholarship through understanding how perceived support and identification act as mediating mechanisms in the relationship between internal communication and employee engagement at the organisational and supervisory level.

Roles of the matrix metalloproteinases in mammary gland development and cancer

Tissue remodeling is a key process involved in normal development, wound healing, bone remodeling, and embryonic implantation, as well as pathological conditions such as tumor invasion and metastasis, and angiogenesis. The degradation of the extracellular matrix that is associated with those processes is mediated by a number of families of extracellular proteinases. These families include the serine proteinases, such as the plasminogen-urokinase plasminogen activator system and leukocyte elastases, the cysteine proteinases, like cathepsin D and L, and the zinc-dependent matrix metalloproteinases (MMPs). Accumulating evidence has highlighted the central role of MMP-driven extracellular matrix remodeling in mammary gland development and breast cancer.

Oncogene-induced basement membrane invasiveness in human mammary epithelial cells

Expression of the intermediate filament protein vimentin, and loss of the cellular adhesion protein uvomorulin (E-cadherin) have been associated with increased invasiveness of established human breast cancer cell lines in vitro and in vivo. In the current study, we have further examined these relationships in oncogenically transformed human mammary epithelial cells. A normal human mammary epithelial strain, termed 184, was previously immortalized with benzo[a]pyrene, and two distinct sublines were derived (A1N4 and 184B5). These sublines were infected with retroviral vectors containing a single or two oncogenes of the nuclear, cytoplasmic, and plasma membrane-associated type (v-rasH, v-rasKi, v -mos, SV40T and c -myc). All infectants have been previously shown to exhibit some aspects of phenotypic transformation. In the current study, cellular invasiveness was determined in vitro using Matrigel, a reconstituted basement membrane extract. Lineage-specific differences were observed with respect to low constitutive invasiveness and invasive changes after infection with ras, despite similar ras-induced transformation of each line. Major effects on cellular invasiveness were observed after infection of the cells with two different oncogenes (v-rasH + SV40T and v -rasH + v -mos). In contrast, the effects of single oncogenes were only modest or negligible. All oncogenic infectants demonstrated increased attachment to laminin, but altered secretion of the 72 kDa and 92 kDa gelatinases was not associated with any aspect of malignant progression. Each of the two highly invasive double oncogene transformants were vimentinpositive and uvomorulin-negative, a phenotype indicative of the epithelial-mesenchymal transition (EMT) previously associated with invasiveness of established human breast cancer cell lines. Weakly invasive untransformed mammary epithelial cells in this study were positive for both vimentin and uvomorulin, suggesting that uvomorulin may over-ride the otherwise vimentin-associated invasiveness.

MMP-9 secretion and MMP-2 activation distinguish invasive and metastatic sublines of a mouse mammary carcinoma system showing epithelial-mesenchymal transition traits

We have investigated the gelatinase profiles and invasiveness of clonal tumour sublines derived from a spontaneously arising mammary tumour in a Balb/cfC3H mouse. The 67NR, 66c14 and 4T1.2 sublines have low, intermediate and high metastatic potential respectively. In Boyden chamber studies, Matrigel invasion was seen to be progressively higher in the more metastatic lines 4T1.2>66c14>67NR, consistent with MMP-2 activation potential, MMP-9 secretion, and migration over either type I or IV collagen, which were low in both 67NR and 66c14 cells compared to 4T1.2 cells. These attributes are consistent with those seen in human breast cancer cell lines which appear to have undergone an epithelial-mesenchymal transition (EMT) as indicated by vimentin expression. We were, however, surprised to find vimentin expression, MT1-MMP expression and stellate Matrigel outgrowth in the non-invasive, non-metastatic 67NR cells, indicating that they had undergone an EMT despite not being invasive. We conclude that the EMT is manifested to differing degrees in these three clonal cell lines, and that the 67NR cells have either undergone a partial EMT or have since lost certain important attributes of the EMT-derived phenotype. This model should prove useful in further characterizing the regulation of MT1-MMP mediated MMP-2 activation and delineating the EMT in breast cancer progression.

Optimizing employee engagement with internal communication : a social exchange perspective

Employee engagement is linked to higher productivity, lower attrition, and improved organizational reputations resulting in increased focus and resourcing by managers to foster an engaged workforce. While drivers of employee engagement have been identified as perceived support, job characteristics, and value congruence, internal communication is theoretically suggested to be a key influence in both the process and maintenance of employee engagement efforts. However, understanding the mechanisms by which internal communication influences employee engagement has emerged as a key question in the literature. The purpose of this research is to investigate whether social factors, namely perceived support and identification, play a mediating role in the relationship between internal communication and engagement. To test the theoretical model, data are collected from 200 non-executive employees using an online self-administered survey. The study applies linear and mediated regression to the model and finds that organizations and supervisors should focus internal communication efforts toward building greater perceptions of support and stronger identification among employees in order to foster optimal levels of engagement.

Discussion on full-scale internal pressure measurements

The wind loading on most structural elements is made up of both an external and internal pressure. Internal pressures are also important for the design of naturally ventilated buildings. The internal pressure is the interaction between the external pressure propagating through the building envelope and any internal plant causing building pressurization. Although the external pressure field can be well defined through a series of wind tunnel tests, modeling complexities makes accurate prediction of the internal pressure difficult. For commercial testing for the determination of design cladding pressures, an internal pressure coefficient is generally assumed from wind loading standards. Several theories regarding the propagation of internal pressures through single and multiple dominant openings have been proposed for small and large flexible buildings (Harris (1990), Holmes, (1979), Liu & Saathoff (1981 ), Vickery (1986, 1994), Vickery & Bloxham (1992), Vickery & Georgiou (1991))...

Model for internal porosity development of different shaped foods

Three particular geometrical shapes of foods were prepared from food materials. Cuboidal (aspect ratio = 1:1, 2:1, 3:1) , cylindrical (length: dameter = 1:1, 2:1, 3:1) and spheres were selected from potato, beans and peas respectively. Internal porosity was determined from solid density (theoretical)and particle density (experimental) during fluidised bed drying at different moisture contents. Solid density was calculated using formulae (conservation of mass and volume) already published in the literature by previous researchers. Determined porosity values were correlated with moisture ratio for different geometrical shapes.

Molecular profiling of human mammary gland links breast cancer risk to a p27(+) cell population with progenitor characteristics

Early full-term pregnancy is one of the most effective natural protections against breast cancer. To investigate this effect, we have characterized the global gene expression and epigenetic profiles of multiple cell types from normal breast tissue of nulliparous and parous women and carriers of BRCA1 or BRCA2 mutations. We found significant differences in CD44+ progenitor cells, where the levels of many stem cell-related genes and pathways, including the cell-cycle regulator p27, are lower in parous women without BRCA1/BRCA2 mutations. We also noted a significant reduction in the frequency of CD44+p27+ cells in parous women and showed, using explant cultures, that parity-related signaling pathways play a role in regulating the number of p27+ cells and their proliferation. Our results suggest that pathways controlling p27+ mammary epithelial cells and the numbers of these cells relate to breast cancer risk and can be explored for cancer risk assessment and prevention.

Generation of uniform plasmas by crossed internal oscillating current sheets : key concepts and experimental verification

The results of comprehensive experimental studies of the operation, stability, and plasma parameters of the low-frequency (0.46 MHz) inductively coupled plasmas sustained by the internal oscillating rf current are reported. The rf plasma is generated by using a custom-designed configuration of the internal rf coil that comprises two perpendicular sets of eight currents in each direction. Various diagnostic tools, such as magnetic probes, optical emission spectroscopy, and an rf-compensated Langmuir probe were used to investigate the electromagnetic, optical, and global properties of the argon plasma in wide ranges of the applied rf power and gas feedstock pressure. It is found that the uniformity of the electromagnetic field inside the plasma reactor is improved as compared to the conventional sources of inductively coupled plasmas with the external flat coil configuration. A reasonable agreement between the experimental data and computed electromagnetic field topography inside the chamber is reported. The Langmuir probe measurements reveal that the spatial profiles of the electron density, the effective electron temperature, plasma potential, and electron energy distribution/probability functions feature a high degree of the radial and axial uniformity and a weak azimuthal dependence, which is consistent with the earlier theoretical predictions. As the input rf power increases, the azimuthal dependence of the global plasma parameters vanishes. The obtained results demonstrate that by introducing the internal oscillated rf currents one can noticeably improve the uniformity of electromagnetic field topography, rf power deposition, and the plasma density in the reactor.

Inductively coupled plasmas sustained by an internal oscillating current

A global electromagnetic model of an inductively coupled plasma sustained by an internal oscillating current sheet in a cylindrical metal vessel is developed. The electromagnetic field structure, profiles of the rf power transferred to the plasma electrons, electron/ion number density, and working points of the discharge are studied, by invoking particle and power balance. It is revealed that the internal rf current with spatially invariable phase significantly improves the radial uniformity of the electromagnetic fields and the power density in the chamber as compared with conventional plasma sources with external flat spiral inductive coils. This configuration offers the possibility of controlling the rf power deposition in the azimuthal direction.