The Roles of Primary Cilia in Cardiovascular Diseases and Cancer

Primary cilia are sensory organelles present in most mammalian cell types and regulate cell cycle and signaling pathways. Biochemical and molecular dysfunctions of primary cilia are associated with a wide range of diseases, including cancer, ciliopathies polycystic kidney disease (PKD, liver disorders, mental retardation, and obesity to cardiovascular diseases. Dysfunction in endothelial cilia contributes to aberrant fluid-sensing and results in vascular disorders, such as hypertension, aneurysm, and atherosclerosis. In this dissertation, the most recent outcomes on the roles of endothelial primary cilia within vascular biology have been summarized. Moreover, we evaluate the correlation between cilia formation or length and cell cycle or division using PKD and cancer epithelia. The results show that these cells were associated with abnormal ploidy and were highly proliferative compared with normal kidney epithelia (NK). Importantly, the cancer epithelial cells show a reduction in the presence and/or length of primary cilia. Restoration of the expression and length of primary cilia in these cells using rapamycin were inversely correlated with cell proliferation. Our data suggest that primary cilia may serve as a novel target in cardiovascular disorder and cancer

Consumer Shopping Behaviour in Relation to Factors Influencing Impulse Buying: A Case of Superstores in Karachi, Pakistan

The significance of understanding impulse purchasing in retail stores was first acknowledged in the marketing literature over fifty years ago. Impulse purchase illustrates any purchase, which a consumer makes throughout it was not planned. This study aimed at highlighting the impact of external and internal factors that influence consumer impulse buying behaviour at super stores in Karachi. This paper contains two variables, i.e. Dependent variable “Consumer impulse buying behaviour” and Independent variables namely external factors (Visual merchandising, Shopping environment and Promotional activities), internal factors (Gender, Credit card and Hedonic motivation). This study attempts to explore the association exists between the variables implicated. This research is quantitative study because there is certain population, among them we tapping the responses of 265 respondents to get their relevant opinions pertaining to our topic. This research examined that consumer’s impulse buying behaviour in super stores are favourable in Karachi. Statistical Packages for Social Sciences (SPSS) tool is used for data analysis. The outcome of the present study verifies that there is a pivotal relationship between visual merchandising, promotional activities, shopping environment, gender, credit card and hedonic motivation with consumer impulse buying behaviour. Consumers are more likely to buy impulsively when they see the colourful surroundings and calm environment not just motivating the consumers to buy involuntarily but also build excitement inside the consumer’s minds. Visual merchandising and hedonic motivation and shopping environment have an important role-play for consumer’s impulse buying. The availability of credit cards and promotional offers also somehow influence consumers for impulse buying. Keywords: Visual Merchandising, Hedonic Motivation, Promotional Activities

The Roles of Primary Cilia in Cardiovascular Diseases

Primary cilia are microtubule-based organelles found in most mammalian cell types. Cilia act as sensory organelles that transmit extracellular clues into intracellular signals for molecular and cellular responses. Biochemical and molecular defects in primary cilia are associated with a wide range of diseases, termed ciliopathies, with phenotypes ranging from polycystic kidney disease, liver disorders, mental retardation, and obesity to cardiovascular diseases. Primary cilia in vascular endothelia protrude into the lumen of blood vessels and function as molecular switches for calcium (Ca2+) and nitric oxide (NO) signaling. As mechanosensory organelles, endothelial cilia are involved in blood flow sensing. Dysfunction in endothelial cilia contributes to aberrant fluid-sensing and thus results in vascular disorders, including hypertension, aneurysm, and atherosclerosis. This review focuses on the most recent findings on the roles of endothelial primary cilia within vascular biology and alludes to the possibility of primary cilium as a therapeutic target for cardiovascular disorders

The Autocrine Role of Proteoglycan-4 (PRG4) in Modulating Osteoarthritic Synoviocyte Proliferation and Expression of Matrix Degrading Enzymes

Background: Lubricin/proteoglycan 4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and superficial zone chondrocytes. Recently, we showed that recombinant human PRG4 (rhPRG4) is a putative ligand for CD44 receptor. rhPRG4-CD44 interaction inhibits cytokine-induced rheumatoid arthritis synoviocyte proliferation. The objective of this study is to decipher the autocrine function of PRG4 in regulating osteoarthritic synoviocyte proliferation and expression of catabolic and pro-inflammatory mediators under basal and interleukin-1 beta (IL-1β)- stimulated conditions. Methods: Cytosolic and nuclear levels of nuclear factor kappa B (NFκB) p50 and p65 subunits in Prg4+/+ and Prg4-/- synoviocytes were studied using western blot. Nuclear translocation of p50 and p65 proteins in osteoarthritis (OA) fibroblast-like synoviocytes (FLS) in response to IL-1β stimulation in the absence or presence of rhPRG4 was studied using DNA binding assays. OA synoviocyte (5000 cells per well) proliferation following IL-1β (20 ng/ml) treatment in the absence or presence of rhPRG4 (50–200 μg/ml) over 48 hours was determined using a colorimetric assay. Gene expression of matrix metalloproteinases (MMPs), tissue inhibitor of metallproteinases-1 (TIMP-1), TIMP-2, IL-1β, IL-6, IL- 8, TNF-α, cycloxygenae-2 (COX2) and PRG4 in unstimulated and IL-1β (1 ng/ml)-stimulated OA synoviocytes, in the presence or absence of rhPRG4 (100 and 200 μg/ml), was studied following incubation for 24 hours. Results: Prg4-/- synoviocytes contained higher nuclear p50 and p65 levels compared to Prg4+/+ synoviocytes (p \u3c 0. 05). rhPRG4 (100 μg/ml) reduced p50 and p65 nuclear levels in Prg4+/+ and Prg4-/- synoviocytes (p \u3c 0.001). Similarly, rhPRG4 (200 μg/ml) inhibited NFκB translocation and cell proliferation in OA synoviocytes in a CD44-dependent manner (p \u3c 0.001) via inhibition of IκBα phosphorylation. IL-1β reduced PRG4 expression in OA synoviocytes and rhPRG4 (100 μg/ml) treatment reversed this effect (p \u3c 0.001). rhPRG4 (200 μg/ml) reduced basal gene expression of MMP-1, MMP-3, MMP-13, IL-6, IL-8, and PRG4 in OA synoviocytes, while increasing TIMP-2 and cycloxygenase-2 (COX2) expression (p \u3c 0.001). rhPRG4 (200 μg/ml) reduced IL-1β induction of MMP-1, MMP-3, MMP-9, MMP-13, IL-6, IL-8, and COX2 expression in a CD44-dependent manner (p \u3c 0.001). Conclusion: PRG4 plays an important anti-inflammatory role in regulating OA synoviocyte proliferation and reduces basal and IL-1β-stimulated expression of catabolic mediators. Exogenous rhPRG4 autoregulates native PRG4 expression in OA synoviocytes

Multi-faceted approach to promote knowledge translation platforms in eastern Mediterranean countries: climate for evidence-informed policy

Senior policymakers, stakeholders and researchers from Algeria, Bahrain, Egypt, Iran, Jordan, Lebanon, Oman, Sudan, Syria, Tunisia, and Yemen participated in this study. Despite the complexity of policymaking processes in countries from this region, the absence of a structured process for decision making, and the limited engagement of policymakers and researchers in knowledge translation (KT) activities, there are windows of opportunity for moving towards more evidence informed policymaking. A recurring positive theme was the development of new national strategic plans. Findings emphasized the complexity of policymaking. Donors, political regimes, economic goals and outdated laws were identified as key drivers

Salivary Cortisol Level Pre and Post MRI Scanning

The measurement of salivary cortisol level has become a reliable method for studying the adrenal cortical function and it is response to different intrinsic and extrinsic factors such as medications and stressful factors.             The aims of this study is to investigate if there is difference between sex and the effect of time of testing on salivary cortisol level, pre and post was scanning, data for cortisol, Salivary Flow Rate (SFR) and PH of saliva were analyzed.             Non-stimulated salivary samples from 24 subjects (8 males, 16 females) pre and post scanning with Magnetic resonance imaging (MRI) was collected and the diurnal variation was taken into consideration for that all the pre and post scanning samples collected at the morning. Salivary cortisol was measured by ELISA technique, PH of saliva was measured by PH meter and salivary flow rate by specific equation.             The results shows there was significant difference in the level of salivary cortisol, SFR and PH of saliva pre and post examination and there was positive correlation with regard to cortisol level and PH of saliva pre and post scanning, just the salivary flow rate showed negative correlation, in addition the results revealed significant difference with regards to the sex of the participant as well as positive correlation between salivary PH and SFR in pretest phase and positive correlation between salivary cortisol level, SFR in post scanning phase.             From the results of this study we can conclude that the exposure to MRI scanning have an effect on Hypothalamic pituitary –adrenal axes and predispose to significant changes in cortisol level post scanning and this difference must be taken into consideration in concern to effect of raising the level of cortisone on other variables

The impact of accreditation of primary healthcare centers: successes, challenges and policy implications as perceived by healthcare providers and directors in Lebanon

BACKGROUND: In 2009, the Lebanese Ministry of Public Health (MOPH) launched the Primary Healthcare (PHC) accreditation program to improve quality across the continuum of care. The MOPH, with the support of Accreditation Canada, conducted the accreditation survey in 25 PHC centers in 2012. This paper aims to gain a better understanding of the impact of accreditation on quality of care as perceived by PHC staff members and directors; how accreditation affected staff and patient satisfaction; key enablers, challenges and strategies to improve implementation of accreditation in PHC. METHODS: The study was conducted in 25 PHC centers using a cross-sectional mixed methods approach; all staff members were surveyed using a self-administered questionnaire whereas semi-structured interviews were conducted with directors. RESULTS: The scales measuring Management and Leadership had the highest mean score followed by Accreditation Impact, Human Resource Utilization, and Customer Satisfaction. Regression analysis showed that Strategic Quality Planning, Customer Satisfaction and Staff Involvement were associated with a perception of higher Quality Results. Directors emphasized the benefits of accreditation with regards to documentation, reinforcement of quality standards, strengthened relationships between PHC centers and multiple stakeholders and improved staff and patient satisfaction. Challenges encountered included limited financial resources, poor infrastructure, and staff shortages. CONCLUSIONS: To better respond to population health needs, accreditation is an important first step towards improving the quality of PHC delivery arrangement system. While there is a need to expand the implementation of accreditation to cover all PHC centers in Lebanon, considerations should be given to strengthening their financial arrangements as well

Rapamycin Treatment Correlates Changes in Primary Cilia Expression with Cell Cycle Regulation in Epithelial Cells

Primary cilia are sensory organelles that regulate cell cycle and signaling pathways. In addition to its association with cancer, dysfunction of primary cilia is responsible for the pathogenesis of polycystic kidney disease (PKD) and other ciliopathies. Because the association between cilia formation or length and cell cycle or division is poorly understood, we here evaluated their correlation in this study. Using Spectral Karyotyping (SKY) technique, we showed that PKD and the cancer/tumorigenic epithelial cells PC3, DU145, and NL20-TA were associated with abnormal ploidy. We also showed that PKD and the cancer epithelia were highly proliferative. Importantly, the cancer epithelial cells had a reduction in the presence and/or length of primary cilia relative to the normal kidney (NK) cells. We then used rapamycin to restore the expression and length of primary cilia in these cells. Our subsequent analyses indicated that both the presence and length of primary cilia were inversely correlated with cell proliferation. Collectively, our data suggest that restoring the presence and/or length of primary cilia may serve as a novel approach to inhibit cancer cell proliferation

ADAMTSL5 and CDH11: putative epigenetic markers for therapeutic resistance in acute lymphoblastic leukemia

Background and objectives: DNA hypermethylation has been linked to poor treatment outcome in childhood acute lymphoblastic leukemia (ALL). Genes differentially methylated in the chemoresponsive pre-B-ALL compared to chemoresistant pre-B-ALL cases provide potential prognostic markers. Methods: DNA methylation profiles of five B-ALL childhood patients who achieved morphological complete remission (chemoresponsive) and five B-ALL patients who did not (chemoresistant) after induction treatments as well as four normal controls were compared on 27 000 CpG sites microarray chips. Subsequently, methylation-specific polymerase chain reaction (MSP) on selected hypermethylated genes was conducted on an additional 37 chemoresponsive and 9 chemoresistant B-ALL samples and 2 normal controls. Results: Both methods were found to be highly correlated. Unsupervised principal component analysis showed that the chemotherapy-responsive and -resistant B-ALL patients could be segregated from one another. Selection of segregated genes at high stringency identified two potential genes (CDH11 and ADAMTSL5). MSP analysis on the larger cohort of samples (42 chemoresponsive, 14 chemoresistant B-ALL samples and 6 normal controls) revealed significantly higher rates of hypermethylation in chemoresistant samples for ADAMTSL5 (93 vs. 38%; p = 0.0001) and CDH11 (79% vs. 40%, p < 0.01). All control cases remained unmethylated. Conclusion: Chemoresistant B-ALL patients are associated with increased methylation in ADAMTSL5 and CDH11. These findings need to be validated in a larger group of patients, and the functional biological and prognostic significance of differential methylation needs to be studied further