Effective supervision of doctoral students in public and population health in Africa: CARTA supervisors' experiences, challenges and perceived opportunities.

The quality and success of postgraduate education largely rely on effective supervision. Since its inception in 2008, the Consortium for Advanced Research Training in Africa (CARTA) has been at the forefront of providing training to both students and supervisors in the field of public and population health. However, there are few studies on supervisors' perceptions on effective doctoral supervision. We used a mostly descriptive study design to report CARTA-affiliated doctoral supervisors' reflections and perceptions on doctoral supervision, challenges and opportunities. A total of 77 out of 160 CARTA supervisors' workshop participants responded to the evaluation. The respondents were affiliated with 10 institutions across Africa. The respondents remarked that effective supervision is a two-way process, involving both supervisor and supervisee's commitment. Some reported that the requirements for effective supervision included the calibre of the PhD students, structure of the PhD programme, access to research infrastructure and resources, supervision training, multidisciplinary exposure and support. Male supervisors have significantly higher number of self-reported PhD graduates and published articles on Scopus but no difference from the females in h-index. We note both student and systemic challenges that training institutions may pursue to improve doctoral supervision in Africa.

[Experiences from PLUS - program for learning and development in Swedish health care]. / Program för EU-utbildade läkare överbryggar kulturella skillnader.

Experiences from PLUS - program for learning and development in Swedish health care In Sweden, more than half of newly registered physicians have been trained outside of the country. Thus, they are not familiar with Swedish culture and the Swedish healthcare system. To support their introduction to a professional carrier in Sweden, in line with the WHO ethical code for recruitment of health personnel, the health care region of Western Sweden established PLUS - program for learning and development in Swedish Health care. A pilot program has now been completed. The physicians had a good biomedical background, but deficiencies in practical skills, cultural insights and knowledge about Swedish health care.  PLUS was based on principles for adult learning with considerable time for reflection and supervision in a group with experienced colleagues. The program was evaluated by an external evaluator, who concluded that the participants felt more secure in their professional role, more familiar with Swedish Health care and better integrated into their health care team. It was concluded that this should lead to improved patient security and better working environment for the physician as well as his/her coworkers.

Correlates of smoking susceptibility among adolescents in a peri-urban area of Nepal: a population-based cross-sectional study in the Jhaukhel-Duwakot Health Demographic Surveillance Site.

BACKGROUND: Susceptibility to smoking is defined as an absence of firm commitment not to smoke in the future or when offered a cigarette by best friends. Susceptibility begins in adolescence and is the first step in the transition to becoming an established smoker. Many scholars have hypothesized and studied whether psychosocial risk factors play a crucial role in preventing adolescent susceptibility to smoking or discourage susceptible adolescents from becoming established smokers. Our study examined sociodemographic and family and childhood environmental factors associated with smoking susceptibility among adolescents in a peri-urban area of Nepal. DESIGN: We conducted a population-based cross-sectional study during October-November 2011 in the Jhaukhel-Duwakot Health Demographic Surveillance Site (JD-HDSS) located in a peri-urban area near Kathmandu, the capital city of Nepal, where tobacco products are easily available. Trained local enumerators conducted face-to-face interviews with 352 respondents aged 14-16. We used stepwise logistic regression to assess sociodemographic and family and childhood environmental factors associated with smoking susceptibility. RESULTS: The percentage of smoking susceptibility among respondents was 49.70% (95% CI: 44.49; 54.93). Multivariable analysis demonstrated that smoking susceptibility was associated with smoking by exposure of adolescents to pro-tobacco advertisements (AOR [adjusted odds ratio] =2.49; 95% CI: 1.46-4.24), the teacher (2.45; 1.28-4.68), adolescents attending concerts/picnics (2.14; 1.13-4.04), and smoking by other family members/relatives (1.76; 1.05-2.95). CONCLUSIONS: Smoking susceptible adolescents are prevalent in the JD-HDSS, a peri-urban community of Nepal. Several family and childhood environmental factors increased susceptibility to smoking among Nepalese non-smoking adolescents. Therefore, intervention efforts need to be focused on family and childhood environmental factors with emphasis on impact of role models smoking, refusal skills in social gatherings, and discussing harmful effects of smoking with family members and during gatherings with friends.

Factors associated with physical growth of children during the first two years of life in rural and urban areas of Vietnam.

BACKGROUND: Differences between urban and rural settings can be seen as a very important example of gaps between groups in a population. The aim of this paper is to compare an urban and a rural area regarding child growth during the first two years of life as related to mother's use of antenatal care (ANC), breastfeeding and reported symptoms of illness. METHODS: The studies were conducted in two Health and Demographic Surveillance Sites, one rural and one urban in Hanoi, Vietnam. RESULTS: We found that children in the urban area grow faster than those in the rural area. There were statistical associations between growth and the education of the mother as well as household resources. There were positive correlations between the number of ANC visits and child growth. We also saw a positive association between growth and early initiation (first hour of life) of breastfeeding but the reported duration of exclusive breastfeeding was not statistically significantly related to growth. Reporting symptoms of illness was negatively correlated to growth, i.e. morbidity is hampering growth. CONCLUSIONS: All predictors of growth discussed in this article, ANC, breastfeeding and illness, are associated with social and economic conditions. To improve and maintain good conditions for child growth it is important to strengthen education of mothers and household resources particularly in the rural areas. Globalization and urbanization means obvious risks for increasing gaps not least between urban and rural areas. Improvement of the quality of programs for antenatal care, breastfeeding and integrated management of childhood illness are also needed in Vietnam.

Bringing evidence to policy to achieve health-related MDGs for all: justification and design of the EPI-4 project in China, India, Indonesia, and Vietnam.

BACKGROUND: The Millennium Development Goals (MDGs) are monitored using national-level statistics, which have shown substantial improvements in many countries. These statistics may be misleading, however, and may divert resources from disadvantaged populations within the same countries that are showing progress. The purpose of this article is to set out the relevance and design of the "Evidence for Policy and Implementation project (EPI-4)". EPI-4 aims to contribute to the reduction of inequities in the achievement of health-related MDGs in China, India, Indonesia and Vietnam through the promotion of research-informed policymaking. METHODS: Using a framework provided by the Commission on the Social Determinants of Health (CSDH), we compare national-level MDG targets and results, as well as their social and structural determinants, in China, India, Indonesia and Vietnam. RESULTS: To understand country-level MDG achievements it is useful to analyze their social and structural determinants. This analysis is not sufficient, however, to understand within-country inequities. Specialized analyses are required for this purpose, as is discussion and debate of the results with policymakers, which is the aim of the EPI-4 project. CONCLUSION: Reducing health inequities requires sophisticated analyses to identify disadvantaged populations within and between countries, and to determine evidence-based solutions that will make a difference. The EPI-4 project hopes to contribute to this goal.

Breastfeeding practices in urban and rural Vietnam.

BACKGROUND: The aim of this study was to describe and compare breastfeeding practices in rural and urban areas of Vietnam and to study associations with possibly influencing person and household factors. This type of study has not been conducted in Vietnam before. METHODS: Totally 2,690 children, born from 1st March 2008 to 30th June 2010 in one rural and one urban Health and Demographic Surveillance Site, were followed from birth to the age of 12 months. Information about demography, economy and education for persons and households was obtained from household surveys. Standard statistical methods including survival and regression analyses were used. RESULTS: Initiation of breastfeeding during the first hour of life was more frequent in the urban area compared to the rural (boys 40% vs. 35%, girls 49% vs. 40%). High birth weight and living in households with large number of assets significantly increased the probability for early initiation of breastfeeding. Exclusive breastfeeding at three months of age was more commonly reported in the rural than in the urban area (boys 58% vs. 46%, girls 65% vs. 53%). The duration of exclusive breastfeeding as well as of any breastfeeding was longer in the rural area than in the urban area (medians for boys 97 days vs. 81 days, for girls 102 days vs. 91 days). The percentages of children with exclusive breastfeeding lasting at least 6 months, as recommended by WHO, were low in both areas. The duration of exclusive breastfeeding was significantly shorter for mothers with three or more antenatal care visits or Caesarean section in both areas. High education level of mothers was associated with longer duration of exclusive breastfeeding in the rural area. No significant associations were found between duration of exclusive breastfeeding and mother's age, household economy indicators or household size. CONCLUSION: Intervention programs with the aim to promote breastfeeding are needed. Mothers should particularly be informed about the importance of starting breastfeeding early and to prolong exclusive breastfeeding. In order to reach the WHO recommendation of six months exclusive breastfeeding, we propose an extended maternity leave legislation to at least six months.

DodaLab: an urban health and demographic surveillance site, the first three years in Hanoi, Vietnam.

RATIONALE: Health and demographic surveillance sites (HDSSs) are important sources for health planning and policy in many low and middle income countries. Almost all HDSSs are in rural settings. The article aims to present the experiences and some concrete results for the first three years of operation of an urban HDSS in Hanoi, Vietnam, and discuss advantages and disadvantages of conducting health studies in HDSSs. DESIGN, POPULATION AND SAMPLE SIZE: The DodaLab urban HDSS was established in 2007 in three communes at different economic levels in Dong Da district, Hanoi, Vietnam. Demographic, social and economic information about 10,000 households and their 37,000 persons was obtained through household interviews. Quarterly follow-up was initiated to provide information about vital events, birth, death and migration. A new household survey was undertaken in 2009. The existing rural HDSS FilaBavi, started in 1999, with 12,000 households and 52,000 persons, was used as the blueprint. CONCLUSIONS: It was possible to establish and run an urban HDSS with experiences from the rural site. The urban and rural contexts are different and demographically, economically and socially complex, but the use of HDSSs can facilitate research beyond very simplified models for comparisons. General statements about external validity of results from the HDSS cannot be made. This issue has to be considered specifically in every situation as an integral part of the research so that the results can be made useful outside the researched HDSS and in performing relevant comparisons.

Physical growth during the first year of life. A longitudinal study in rural and urban areas of Hanoi, Vietnam.

BACKGROUND: Good infant growth is important for future health. Assessing growth is common in pediatric care all over the world, both at the population and individual level. There are few studies of birth weight and growth studies comparing urban and rural communities in Vietnam. The first aim is to describe and compare the birth weight distributions and physical growth (weight and length) of children during their first year in one rural and one urban area of Hanoi Vietnam. The second aim is to study associations between the anthropometric outcomes and indicators of the economic and educational situations. METHODS: Totally 1,466 children, born from 1st March, 2009 to June 2010, were followed monthly from birth to 12 months of age in two Health and Demographic Surveillance Sites; one rural and one urban. In all, 14,199 measurements each of weight and length were made. Birth weight was recorded separately. Information about demographic conditions, education, occupation and economic conditions of persons and households was obtained from household surveys. Fractional Polynomial models and standard statistical methods were used for description and analysis. RESULTS: Urban infants have higher birth weight and gain weight faster than rural infants. The mean birth weight for urban boys and girls were 3,298 grams and 3,203 grams as compared to 3,105 grams and 3,057 grams for rural children. At 90 days, the urban boys were estimated to be 4.1% heavier than rural boys. This difference increased to 7.2% at 360 days. The corresponding difference for girls was 3.4% and 10.5%. The differences for length were comparatively smaller. Both birth weight and growth were statistically significantly and positively associated with economic conditions and mother education. CONCLUSION: Birth weight was lower and the growth, weight and length, considerably slower in the rural area, for boys as well as for girls. The results support the hypothesis that the rather drastic differences in maternal education and economic conditions lead to poor nutrition for mothers and children in turn causing inferior birth weight and growth.

Urban - rural disparities in antenatal care utilization: a study of two cohorts of pregnant women in Vietnam.

BACKGROUND: The use of antenatal care (ANC) varies between countries and in different settings within each country. Most previous studies of ANC in Vietnam have been cross-sectional, and conducted in rural areas before the year 2000. This study aims to compare the pattern and the adequacy of ANC used in rural and urban Vietnam following two cohorts of pregnant women. METHODS: A comparative study with two cohorts comprising totally 2132 pregnant women were followed in two health and demographic surveillance sites, one rural and one urban in Hanoi province, Vietnam. The women were quarterly interviewed using a structured questionnaire until delivery. The primary information obtained was the number and the content of ANC visits. RESULTS: Almost all women reported some use of ANC. The average number of visits was much lower in the rural setting (4.4) than in the urban (7.7). In the rural area, 77.2% of women had at least three visits and 69.1% attended ANC during the first trimester. The corresponding percentages for the urban women were 97.2% and 97.2%. Only 20.3% of the rural women compared to 81.1% of the urban women received all core ANC services. As a result, the adequate use of ANC was 5.2 times in the urban than in the rural setting (78.3% compared to 15.2%). Nearly all women received ultrasound examination during pregnancy with a mean value of 6.0 scans per woman in the urban area and 3.5 in the rural. Most rural women used ANC at commune health centres and private clinics while urban women mainly visited public hospitals. Expenditure related to ANC utilization for the urban women was 7.1 times that for the urban women. CONCLUSION: The women in the rural area attended ANC later, had fewer visits and received much fewer services than urban women. The large disparity in ANC adequacy between the two settings suggests special attention for the ANC programme in rural areas focusing on its content. Revision and enforcement of the national guidelines to improve the behaviour and practice of both users and providers are necessary.

Macrophages exposed to hypoxia secrete proteoglycans for which LDL has higher affinity.

Macrophages are prominent in hypoxic areas of atherosclerotic lesions. Their secreted proteoglycans (PG) can modulate the retention of lipoproteins as well as the activity of enzymes, cytokines, and growth factors involved in atherogenesis. Versican appears to be one of the main extracellular matrix components binding LDL in the arterial intima. We have recently shown that hypoxia increases versican and perlecan expression in macrophages, and that this increase was regulated by the hypoxia inducible factor (HIF). Here we report effects of hypoxia on human monocyte-derived macrophage (HMDM) secreted glycosaminoglycans (GAG), and its interaction with LDL. After 24 h exposure to 0.5% O2 (hypoxia), metabolically labeled GAG of secreted PG had higher affinity for LDL compared to 21% O2 (control cells). GAG secreted by HMDM in hypoxia were found to be more sulfated and longer which might be responsible for the increased affinity of LDL for these GAG chains. These results indicate that hypoxia induced changes in macrophage GAG biosynthesis have important consequences for the interaction with LDL. If present in vivo, an augmented association of GAG with LDL might contribute to the development of atherosclerosis in hypoxic intima.

Hypoxic regulation of secreted proteoglycans in macrophages.

Macrophages are prominent in hypoxic areas of atherosclerotic lesions, and their secreted proteoglycans (PG), such as versican, can modulate the retention of lipoproteins and the activity of enzymes, cytokines, and growth factors involved in atherogenesis. In this study, we report the effects of hypoxia on PG secreted by human monocyte-derived macrophages (HMDM) and the potential regulation by the transcription factor hypoxia-inducible factor (HIF-1alpha and HIF-2alpha). We found that versican co-localized with HIF-1alpha in macrophage-rich areas in human advanced atherosclerotic lesions. Versican and perlecan mRNA expression increased after exposure to 0.5% O(2) (hypoxia) compared with 21% O(2) (control cells). Using precursors to GAG biosynthesis combined with immunoabsorption with a versican antibody an increased versican synthesis was detected at hypoxia. Furthermore, siRNA knockdown of HIF-1alpha and HIF-2alpha in THP-1 cells showed that the hypoxic induction of versican and perlecan mRNA expression involved HIF signaling. Versican expression was co-regulated by HIF-1alpha and HIF-2alpha but expression of perlecan was influenced only by HIF-1alpha and not by HIF-2alpha knockdown. The results show that oxygen concentration is an important modulator of PG expression in macrophages. This may be a novel component of the complex role of macrophages in atherosclerosis.

Hypoxia increases macrophage motility, possibly by decreasing the heparan sulfate proteoglycan biosynthesis.

Macrophages are recruited and retained in hypoxic sites in atherosclerotic lesions and tumors. Furthermore, macrophages are suggested to be a major source of HSPG synthesis in atherosclerotic lesions. HSPG are, among other things, known to regulate cell motility, cell adhesion, and receptor interaction. The aim of this study was to investigate the effect of hypoxia on HSPG expression and macrophage motility. We also explored the potential regulation of HSPG by the transcription factor HIF-1alpha. The nondirected cell motility was increased in HMDM after 24 h exposure to hypoxia (0.5% O(2)) compared with normal cell culture condition (21% O(2)). Enzymatic degradation of HS GAG further increased the motility of the HMDM in hypoxia, indicating a role of reduced cell-associated HSPG in the increased HMDM motility. HMDM exposed to 24 h of hypoxia had lower mRNA expressions of syndecan-1 and -4 compared with cells exposed to normal cell culture conditions. Protein levels of syndecan-1 were also decreased significantly in response to hypoxia, and cells subjected to hypoxia had lower mRNA expression for key enzymes involved in HS biosynthesis. In addition, hypoxia was found to reduce the relative content of HS GAG. Transfecting THP-1 cells with siHIF-1alpha indicated that this transcription factor was not involved in the hypoxia-induced modifications of HSPG expression. Given the documented multiple functions of HSPG in macrophage behavior, the hypoxia-induced modifications of HSPG may be of relevance for the development of atherosclerotic lesions and tumor progression.

Fatty acid-induced atherogenic changes in extracellular matrix proteoglycans.

PURPOSE OF REVIEW: Nonesterified fatty acids change the expression and properties of the extracellular matrix proteoglycans of arterial and hepatic cells. We review how this may contribute to arterial disease in insulin resistance and type 2 diabetes. RECENT FINDINGS: Elevated nonesterified fatty acids characterize the dyslipidemia of insulin resistance and type 2 diabetes. In hepatocytes high levels of fatty acids cause changes in proteoglycans leading to a matrix with decreased affinity for VLDL remnants. Furthermore, liver proteoglycans from insulin resistant hyperlipidemic Zucker rats showed alterations also associated with decreased remnant affinity. In arterial smooth muscle cells overexposure to fatty acids augmented expression of matrix proteoglycans for which LDL showed increased affinity. Fatty acids appeared to compromise insulin signaling by protein kinase C activation. The observed fatty acid-induced changes in matrix proteoglycans in liver and arteries can be an important component of the atherogenicity of the dyslipidemia of insulin resistance and type 2 diabetes. SUMMARY: Overexposure to fatty acids can contribute to generate a remnant-rich dyslipidemia and to precondition the arterial intima for lipoprotein deposition via changes in expression of matrix proteoglycans. Normalizing fatty acid should be a key target in treatment of the atherogenic dyslipidemia of insulin resistance.

Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development.

During vascular development, endothelial platelet-derived growth factor B (PDGF-B) is critical for pericyte recruitment. Deletion of the conserved C-terminal heparin-binding motif impairs PDGF-BB retention and pericyte recruitment in vivo, suggesting a potential role for heparan sulfate (HS) in PDGF-BB function during vascular development. We studied the participation of HS chains in pericyte recruitment using two mouse models with altered HS biosynthesis. Reduction of N-sulfation due to deficiency in N-deacetylase/N-sulfotransferase-1 attenuated PDGF-BB binding in vitro, and led to pericyte detachment and delayed pericyte migration in vivo. Reduced N-sulfation also impaired PDGF-BB signaling and directed cell migration, but not proliferation. In contrast, HS from glucuronyl C5-epimerase mutants, which is extensively N- and 6-O-sulfated, but lacks 2-O-sulfated L-iduronic acid residues, retained PDGF-BB in vitro, and pericyte recruitment in vivo was only transiently delayed. These observations were supported by in vitro characterization of the structural features in HS important for PDGF-BB binding. We conclude that pericyte recruitment requires HS with sufficiently extended and appropriately spaced N-sulfated domains to retain PDGF-BB and activate PDGF receptor beta (PDGFRbeta) signaling, whereas the detailed sequence of monosaccharide and sulfate residues does not appear to be important for this interaction.

Fatty acids cause alterations of human arterial smooth muscle cell proteoglycans that increase the affinity for low-density lipoprotein.

OBJECTIVE: The dyslipidemia of insulin resistance, with high levels of albumin-bound fatty acids, is a strong cardiovascular disease risk. Human arterial smooth muscle cell (hASMC) matrix proteoglycans (PGs) contribute to the retention of apoB lipoproteins in the intima, a possible key step in atherogenesis. We investigated the effects of high NEFA levels on the PGs secreted by hASMCs and whether these effects might alter the PG affinity for low-density lipoprotein. METHODS AND RESULTS: hASMC exposed for 72 hours to high concentrations (800 micromol/L) of linoleate (LO) or palmitate upregulated the core protein mRNAs of the major PGs, as measured by quantitative PCR. Insulin (1 nmol/L) and the PPARgamma agonist rosiglitazone (10 micromol/L) blocked these effects. In addition, high LO increased the mRNA levels of enzymes required for glycosaminoglycan (GAG) synthesis. Exposure to NEFA increased the chondroitin sulfate:heparan sulfate ratio and the negative charge of the PGs. Because of these changes, the GAGs secreted by LO-treated cells had a higher affinity for human low-density lipoprotein than GAGs from control cells. Insulin and rosiglitazone inhibited this increase in affinity. CONCLUSIONS: The response of hASMC to NEFA could induce extracellular matrix alterations favoring apoB lipoprotein deposition and atherogenesis.

IFNgamma regulates PDGF-receptor alpha expression in macrophages, THP-1 cells, and arterial smooth muscle cells.

The recruitment of monocyte-derived macrophages (MDMs) and arterial smooth muscle cells (ASMCs) contributes to inflammation and development of intimal hyperplasia during atherosclerosis. Platelet-derived growth factor (PDGF) is a potent mitogen for SMC, signalling through PDGF-receptor subunits alpha (Ralpha) and beta (Rbeta). We have previously found that interferon gamma (IFNgamma) upregulates PDGF-Ralpha mRNA expression in human MDM (hMDM) which causes an increased migration towards PDGF. In the present study, we found that IFNgamma mediated an upregulation of PDGF-Ralpha mRNA also in THP-1 cells. The induction of PDGF-Ralpha in both hMDM and THP-1 cells was caused by STAT1 binding to the PDGF-Ralpha promoter. In human ASMCs, IFNgamma again stimulated a transient STAT1-binding to the PDGF-Ralpha promoter. However, this was not followed by an upregulation of PDGF-Ralpha mRNA. IFNgamma-stimulation resulted in augmented expression of PDGF-Ralpha protein in differentiated hMDM. Early hMDM only expressed an immature and not fully glycosylated form of the PDGF-Ralpha protein. In contrast, THP-1 cells did not synthesize PDGF-Ralpha protein, implying further posttranscriptional inhibition. Our results contribute to a better understanding of the complex regulation of PDGF-Ralpha expression and how proinflammatory factors may contribute to PDGF-related hyperplasia in vascular diseases.

Fatty acids induce increased granulocyte macrophage-colony stimulating factor secretion through protein kinase C-activation in THP-1 macrophages.

Insulin resistance and type 2 diabetes are associated with elevated circulating levels of nonesterified FA (NEFA) and lipoprotein remnants. The dyslipidemia is an important contributor to the excess arterial disease associated with insulin resistance and type 2 diabetes, but the mechanisms involved are elusive. In the present study we examined the effect of NEFA on macrophages. For this purpose, we utilized human macrophages, prepared by treating THP-1 monocytes with phorbol ester. We found that albumin-bound NEFA at physiological levels increase the secretion of granulocyte macrophage-colony stimulating factor (GM-CSF) by the THP-1 macrophages in a dose-dependent manner. The effect was registered as an increase in mRNA, and the amount of GM-CSF secreted correlated with the accumulation of TAG and DAG in the cell. The NEFA-induced rise in GM-CSF appeared to be mediated by activation of protein kinase C, probably acting on extracellular signal-regulated kinases 1 and 2 and being calcium dependent. We speculate that increased secretion of GM-CSF by resident macrophages in the intima exposed chronically to high levels of NEFA, such as those present in insulin resistance, may contribute to a proatherogenic response of arterial cells.

Hypoxia increases 25-hydroxycholesterol-induced interleukin-8 protein secretion in human macrophages.

Interleukin-8 (IL-8) is a chemotactic factor for T-lymphocytes and smooth muscle cells and may therefore have an important effect in atherogenesis. It is secreted from oxysterol-containing foam cells which have been found in hypoxic zones in atherosclerotic plaques. The aim of this study was to investigate the effect of hypoxia on the secretion of IL-8 by oxysterol-stimulated macrophages. Hypoxia enhances 25-hydroxycholesterol (25-OH-chol)-induced IL-8 secretion in human monocyte-derived macrophages. The effect is most pronounced when macrophages are incubated with low concentrations of 25-OH-chol. Both 25-OH-chol and hypoxia increases the intracellular level of the signalling molecule hydrogen peroxide (H(2)O(2)). This event coincided with an enhanced binding of the transcription factor c-jun to the IL-8 gene promoter and an increased IL-8 mRNA expression in hypoxic macrophages. These observations suggest that similar intracellular signalling pathways are used for both 25-OH-chol-induced IL-8 expression and hypoxia-induced IL-8 expression. Thus, hypoxia in atherosclerotic plaques may increase the secretion of IL-8 from oxysterol-containing foam cells, which subsequently may accelerate the progression of atherosclerosis.

The extracellular matrix on atherogenesis and diabetes-associated vascular disease.

Atherosclerosis is remarkably increased in type 2 diabetes suggesting that mechanisms causing arterial lesion are enhanced by the metabolic disturbances of insulin resistance (IR) and diabetes. Several lines of research suggest that processes taking place in the arterial intima extracellular matrix may be part of a shared pathogenic mechanism. The intima extracellular matrix is where atherogenesis takes place. This layer contains fibrilar macromolecules like collagens, proteoglycans (PGs), hyaluronate, and extracellular multi-domain proteins. Specific interaction of lysine, arginine-rich segments of the apoB-100 lipoproteins, LDL, IDL and Lp (a), with the negatively charged glycosaminoglycans (GAGs) of PGs cause retention of the lipoproteins, one of the initiation process of atherogenesis. Such interactions cause structural modifications of the lipid and protein moieties of the lipoproteins that appear to increase their susceptibility to proteases, phospholipases and free radical-mediated processes. The association of apoB-lipoproteins, specially small and dense LDL, with intima PGs increases their uptake by macrophages and human arterial smooth muscle cells (HASMC) leading to 'foam cell' formation. In vitro, elevated levels of non-esterified fatty acids (NEFA) alter the matrix of endothelial cells basement membrane making them more permeable to macromolecules. NEFA cause changes in the expression of genes controlling the PGs composition of the PGs secreted by HASMC causing formation of a matrix with high affinity for LDL. These results lead us to speculate that an important component of the dyslipidemia of IR and type 2 diabetes, chronic high NEFA, may contribute to cellular alterations that cause changes of the arterial intima extracellular matrix. Such changes may increase the atherogenicity of the retention of apoB lipoproteins in the intima and contribute to the systemic alteration of the arterial wall frequently observed in IR and type 2 diabetes.