A birth cohort study in the Middle East: the Qatari birth cohort study (QBiC) phase I.

BACKGROUND: The latest scientific reports raise concerns about the rapidly increasing burden of chronic diseases in the state of Qatar. Pregnant Qatari women often confront complications during pregnancy including gestational diabetes, hypertension, abortion and stillbirth. The investigation of early life environmental, genetic, nutritional and social factors that may affect lifelong health is of great importance. Birth cohort studies offer a great opportunity to address early life hazards and their possible long lasting effects on health. METHODS/DESIGN: The Qatari Birth Cohort study is the first mother-child cohort study in the Middle East Area that aims to assess the synergetic role of environmental exposure and genetic factors in the development of chronic disease and monitor woman and child health and/or obstetric characteristics with high prevalence. The present manuscript describes the recruitment phase of the study (duration: 2 years; expected number: 3000 families), where the pregnant Qatari women and their husbands are being contacted before the 15th week of gestation at the Primary Health Care Centers. The consented participants are interviewed to obtain information on several factors (sociodemographic characteristics, dietary habits, occupational/environmental exposure) and maternal characteristics are assessed based on anthropometric measurements, spirometry, and blood pressure. Pregnant women are invited to provide biological samples (blood and urine) in each trimester of their pregnancy, as well as cord blood at delivery. Fathers are also asked to provide biological samples. DISCUSSION: The present study provides invaluable insights into a wide range of early life factors affecting human health. With a geographical focus on the Middle East, it will be a resource for information to the wider scientific community and will allow the formulation of effective policies with a primary focus on public health interventions for maternal and child health.

Study protocol: Mother and Infant Nutritional Assessment (MINA) cohort study in Qatar and Lebanon.

BACKGROUND: The Middle East and North Africa region harbors significant proportions of stunting and wasting coupled with surging rates of non-communicable diseases (NCDs). Recent evidence identified nutrition during the first 1000 days of life as a common denominator not only for optimal growth but also for curbing the risk of NCDs later in life. The main objective of this manuscript is to describe the protocol of the first cohort in the region to investigate the association of nutrition imbalances early in life with birth outcomes, growth patterns, as well as early determinants of non-communicable diseases. More specifically the cohort aims to 1) examine the effects of maternal and early child nutrition and lifestyle characteristics on birth outcomes and growth patterns and 2) develop evidence-based nutrition and lifestyle guidelines for pregnant women and young children. METHODS/DESIGN: A multidisciplinary team of researchers was established from governmental and private academic and health sectors in Lebanon and Qatar to launch the Mother and Infant Nutritional Assessment 3-year cohort study. Pregnant women (n = 250 from Beirut, n = 250 from Doha) in their first trimester are recruited from healthcare centers in Beirut, Lebanon and Doha, Qatar. Participants are interviewed three times during pregnancy (once every trimester) and seven times at and after delivery (when the child is 4, 6, 9, 12, 18, and 24 months old). Delivery and birth data is obtained from hospital records. Data collection includes maternal socio-demographic and lifestyle characteristics, dietary intake, anthropometric measurements, and household food security data. For biochemical assessment of various indicators of nutritional status, a blood sample is obtained from women during their first trimester. Breastfeeding and complementary feeding practices, dietary intake, as well as anthropometric measurements of children are also examined. The Delphi technique will be used for the development of the nutrition and lifestyle guidelines. DISCUSSION: The Mother and Infant Nutritional Assessment study protocol provides a model for collaborations between countries of different socio-economic levels within the same region to improve research efficiency in the field of early nutrition thus potentially leading to healthier pregnancies, mothers, infants, and children.

A Telephone-Based Tobacco Cessation Program in the State of Qatar: Protocol of a Feasibility Study.

In Qatar, tobacco is the leading preventable cause of death and disease. Telephone-based interventions for smoking are cost-effective and scalable interventions that are effective in promoting smoking behavior change. While many countries have implemented these services within their tobacco control programs, there is a distinct dearth of a telephone-based smoking cessation intervention that is adapted and tailored to meet the needs of people who smoke in Qatar. This study presents the protocol of a primary health care center integrated smoking quitline program in Qatar. Participants will be recruited from seven smoking clinics (recruitment sites). Trained clinic staff will provide brief advice on quitting followed by a referral to the quitline. Eligible participants (male smokers over 18 years of age) will complete baseline questionnaires and receive five weekly proactive counseling calls, an end-of-treatment assessment (approx. 1 week after Session 5), and 1- and 3-month follow-up assessments. The main aim of this study is to assess the feasibility and acceptability, which include the recruitment and retention rate, compliance to pharmacotherapy, and participant satisfaction. This is the first study to integrate an evidence-based smoking cessation intervention delivered via telephone within the healthcare system in Qatar. If effective, results can inform the development of a large-scale telephone-based program that widely reaches users of tobacco in Qatar as well as in the Middle East.

The effect of vitamin D supplementation on the glycemic control of pre-diabetic Qatari patients in a randomized control trial.

BACKGROUND: Vitamin D deficiency is associated with indicators of pre-diabetes including, insulin resistance, ß-cell dysfunction and elevated plasma glucose with controversial findings from current trials. This study aims to investigate the long-term effect of vitamin D on glucose metabolism and insulin sensitivity in pre-diabetic and highly vitamin-deficient subjects. METHODS: One hundred thirty-two participants were randomized to 30,000 IU vitamin D weekly for 6 months. Participants underwent oral glucose tolerance test (OGTT) at 3-month intervals to determine the change in plasma glucose concentration at 2 h after 75 g OGTT (2hPCG). Secondary measurements included glycated hemoglobin, fasting plasma glucose and insulin, post-prandial insulin, indices of insulin sensitivity (HOMA-IR, Matsuda Index), ß-cell function (HOMA-ß, glucose and insulin area under the curve (AUC), disposition and insulinogenic indices), and lipid profile. RESULTS: A total of 57 (vitamin D) and 75 (placebo) subjects completed the study. Mean baseline serum 25(OH) D levels were 17.0 ng/ml and 14.9 ng/ml for placebo and vitamin D group, respectively. No significant differences were observed for 2hPC glucose or insulin sensitivity indices between groups. HOMA-ß significantly decreased in the vitamin D group, while area under curve for glucose and insulin showed a significant reduction in ß-cell function in both groups. Additionally, HOMA-ß was found to be significantly different between control and treatment group and significance persisted after adjusting for confounding factors. CONCLUSION: Vitamin D supplementation in a pre-diabetic and severely vitamin-deficient population had no effect on glucose tolerance or insulin sensitivity. The observed reduction in ß-cell function in both placebo and vitamin D groups could be attributed to factors other than supplementation. TRIAL REGISTRATION: NCT02098980, 28/03/2014 (www.clinicaltrials.gov).

Defects in activation of nitric oxide synthases occur during delayed angiogenesis in aging.

Angiogenesis, the formation of new vessels from pre-existing vasculature, is impaired in aging. This is due, in part, to a lack of regulatory molecules such as nitric oxide (NO). We wished to test the hypothesis that there are deficits in the pathways that mediate NO production during angiogenesis (as defined by fibrovascular invasion into a polyvinyl alcohol (PVA) sponge implant), in aged mice in comparison to young mice. Sponges were implanted subcutaneously in young (6-8 months old, n=11) and aged (23-25 months old, n=13) mice and sampled at 14 and 19 days. Sections from the implants were stained with antibodies against vascular endothelial growth factor receptor 2 (VEGFR-2), Akt, phosphorylated Akt (p-Akt), endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS), inducible NOS (iNOS), and 3-nitrotyrosine (3-NT, a marker for nitrosylated proteins). Expression of VEGFR-2 was similar in the sponges of young and aged mice. Moreover, there were no significant differences in levels of Akt or its phosphorylated form in sponges from young and aged mice at 14 and 19 d. In marked contrast, levels of eNOS, p-eNOS and iNOS were significantly decreased in sponges from aged mice relative to young mice (p<0.02 for eNOS, p-eNOS and <0.01 for iNOS between young and aged mice). Concomitantly, there was diminished expression of 3-NT in the sponges from aged mice (p<0.05). Our data indicate that defects in the activation of nitric oxide synthases result in decreased NO production in aged tissues relative to young tissues. We propose that the subsequent lack of NO contributes to impaired angiogenesis in aging.

Atherosclerotic lesions in the common coronary arteries of ApoE knockout mice.

OBJECTIVE: The present study describes the distribution of atherosclerotic lesions in the coronary arteries of chow-fed 60-week-old male ApoE(-/-), 17-beta-estradiol-treated ApoE(-/-), and wild-type mice. METHODS AND RESULTS: The histologic examination of coronary arteries in 12 ApoE(-/-) and 6 wild-type mice, in contrast to the distribution of atherosclerosis in human coronary arteries, reveals that the major lesions in the mouse are located in the valve sinus, including the origins of the coronary arteries. These retrovalvular lesions either stop abruptly at the orifice of the common coronary artery or extend a short distance onto the arterial trunks. The first segment and first branch of all the major coronary arteries, the usual sites of disease in humans, are protected from disease. Although the arterial trunks and the first level branches are free of disease, we found approximately four independent lesions per heart. Independent lesions are present in the heart in smaller, intramyocardial vessels. These lesions are comprised predominantly of macrophages and proteoglycan and exhibit little extracellular lipid. In some cases, the independent lesions occlude the lumen without evidence of myocardial infarct in the surrounding tissue. CONCLUSIONS: The specificity of the localization of lesions in certain segments of the murine coronary tree suggests that fundamental properties found at different branch levels determine lesion location.

Impaired angiogenesis in aging is associated with alterations in vessel density, matrix composition, inflammatory response, and growth factor expression.

It is generally accepted that angiogenesis is delayed in aging. To define the effects of age on the neovascular response, polyvinyl alcohol sponges were implanted SC in young (6-8 months old, n=11) and aged (23-25 months old, n=13) mice and sampled at 14 and 19 days. Angiogenic invasion was significantly delayed in aged mice at 14d relative to young at 14d (% area of invasion 9.0 +/- 3.7 vs 19.0 +/- 5.6; p=0.02). Although microvessel morphology and basement membrane composition were similar between the age groups, a significant decrease in capillary density was noted in aged tissues at 14d (7.5 +/- 4.1) and 19d (12.1 +/- 2.8) relative to young at 14d (18.7 +/- 2.3) (p<0.01 A14d vs Y14d). In comparison to young at 14d, the inflammatory response was decreased by 43 +/- 2.9% and 36 +/- 7.8% in aged mice at 14d and 19d, respectively. Tissues of aged mice showed less newly deposited collagen. There was a lack of expression of transforming growth factor-beta1 (TGF-beta1) and vascular endothelial growth factor (VEGF) in aged mice at 14d (0.63 +/- 0.3) and 19d (1.14 +/- 0.5) vs young at 14d (1.92 +/- 0.5) (p< or =0.01 A14d vs Y14d for VEGF). However, similar production of VEGF receptor2 was observed. In contrast to young mice, there was significantly increased expression of thrombospondin-2 (TSP-2) in aged mice from 14d (14.6 x 10(3) +/- 7.3 x 10(3)) to 19d (34.9 x 10(3) +/- 17 x 10(3)). We conclude that angiogenesis in aging is not merely delayed, but is altered due to multiple impairments.

Inhibited angiogenesis in aging: a role for TIMP-2.

Factors responsible for age-associated impairment of angiogenesis are poorly understood. We observed that in aged mice, new fibrovascular tissue within subcutaneous polyvinyl alcohol sponges expressed more tissue inhibitor of metalloproteinases (TIMP)-2 than did corresponding tissue from young mice. In complementary studies in vitro, we utilized young and aged human microvascular endothelial cell lines (hmEC36 and hmEC90, respectively) and compared their morphogenetic capacity within three-dimensional collagen. HmEC90 exhibited poor formation of tubular, capillary-like structures in vitro, diminished expression of active matrix metalloproteinase (MMP)-2, and similar or lesser amounts of MT1-MMP relative to hmEC36. Correspondingly, the MMP inhibitor GM6001 decreased tubulogenesis by hmEC36 to levels observed for hmEC90. In vitro, hmEC90 expressed similar quantities of TIMP-1, but more TIMP-2 than did hmEC36. Accordingly, purified TIMP-2 inhibited tubulogenesis by hmEC36. Collectively, our studies indicate that elevated levels of TIMP-2 modulate decreased angiogenesis in aged tissues, most likely via TIMP-2-mediated inhibition of MMP-2 and MT1-MMP.

Relationship between insulin resistance and plasma vitamin D in adults.

A recent relationship between vitamin D deficiency and the risk of type 2 diabetes mellitus (T2DM) and insulin resistance has been established through several studies. Research suggests a correlation between serum vitamin D and glycemic status measures. The aim of this study was to investigate the relationship between the plasma vitamin D levels (25[OH]D) and the factors linked to insulin resistance in a representative sample of Canadians ranging in age from 16-79 years. Data were used from the Canadian Health Measures Survey where direct measures of health and wellness were reported from 1,928 subjects. These data were gathered from March 2007-February 2009 at 15 sites selected through a multistage sampling strategy. An inverse relationship between insulin resistance and plasma vitamin D level in both men and women was observed. This study provides additional evidence for the role of vitamin D in T2DM. If causally associated, the supplementation of vitamin D may help in preventing insulin resistance and subsequent T2DM.

The global relationship between the prevalence of diabetes mellitus and incidence of tuberculosis: 2000-2012.

BACKGROUND: The dual burden of tuberculosis (TB) and diabetes mellitus (DM) has increased over the past decade with DM prevalence increasing in countries already afflicted with a high burden of TB. The coexistence of the two conditions presents a serious threat to global public health. OBJECTIVE: The present study examines the global relationship between the prevalence of DM and the incidence of TB to evaluate their coexistence worldwide and their contribution to one another. METHODS: This is an ecological longitudinal study covering the period between years 2000 to 2012. We utilized data from the WHO and World Bank sources and International Diabetes Federation to estimate prevalence of DM (%) and the incidence of TB (per 100,000). Measures of central tendency and dispersion as well as the harmonic mean and linear regression were used for different WHO regions. The association between DM prevalence and TB incidence was examined by quartile of DM prevalence. RESULTS: The worldwide average (±S.D.) prevalence of DM within the study period was 6.6±3.8% whereas TB incidence was 135.0±190.5 per 100,000. DM prevalence was highest in the Eastern Mediterranean (8.3±4.1) and West Pacific (8.2±5.6) regions and lowest in the Africa (3.5±2.6). TB incidence was highest in Africa (313.1±275.9 per 100,000) and South-East Asia (216.7±124.9) and lowest in the European (46.5±68.6) and American (47.2±52.9) regions. Only countries with high DM prevalence (>7.6%) showed a significant positive association with TB incidence (r=0.17, p=0.013). CONCLUSION: A positive association between DM and TB may exist in some - but not all - world regions, a dual burden that necessitates identifying the nature of this coexistence to assist in developing public health approaches that curb their rising burden.

Change in the structures, dynamics and disease-related mortality rates of the population of Qatari nationals: 2007-2011.

BACKGROUND: Developing effective public health policies and strategies for interventions necessitates an assessment of the structure, dynamics, disease rates and causes of death in a population. Lately, Qatar has undertaken development resurgence in health and economy that resulted in improving the standard of health services and health status of the entire Qatari population (i.e., Qatari nationals and non-Qatari residents). No study has attempted to evaluate the population structure/dynamics and recent changes in disease-related mortality rates among Qatari nationals. OBJECTIVE: The present study examines the population structure/dynamics and the related changes in the cause-specific mortality rates and disease prevalence in the Qatari nationals. METHODS: This is a retrospective, analytic descriptive analysis covering a period of 5years (2007-2011) and utilizes a range of data sources from the State of Qatar including the population structure, disease-related mortality rates, and the prevalence of a range of chronic and infectious diseases. Factors reflecting population dynamics such as crude death (CDR), crude birth (CBR), total fertility (TFR) and infant mortality (IMR) rates were also calculated. RESULTS: The Qatari nationals is an expansive population with an annual growth rate of ∼4% and a stable male:female ratio. The CDR declined by 15% within the study period, whereas the CBR was almost stable. The total disease-specific death rate, however, was decreased among the Qatari nationals by 23% due to the decline in mortality rates attributed to diseases of the blood and immune system (43%), nervous system (44%) and cardiovascular system (41%). There was a high prevalence of a range of chronic diseases, whereas very low frequencies of the infectious diseases within the study population. CONCLUSION: Public health strategies, approaches and programs developed to reduce disease burden and the related death, should be tailored to target the population of Qatari nationals which exhibits characteristics that vary from the entire Qatari population.

Prevalence of vitamin d insufficiency in qatar: a systematic review.

Qatar has a high burden of chronic diseases including obesity, cardiovascular disease and type 2 diabetes mellitus. Low serum vitamin D levels have been implicated in the development and progression of a range of these chronic conditions. The prevalence of vitamin D insufficiency or deficiency in the general population of Qatar has still not been investigated. The aim of this study was to carry out a systematic review of published studies documenting the prevalence of vitamin D insufficiency or deficiency in the Qatari population. A search strategy was developed for online databases (PubMed, Ovid MEDLINE, Embase and Embase Classic) between 1980 to the last week of August 2012, and bibliographies of the included studies were further searched for additional reports. Search terms used were QATAR and VITAMIN D. Studies reporting the serum levels of vitamin D in several Qatari sub-populations were identified. Weighted-average vitamin D serum levels and prevalence of low vitamin D status (<75 nmol/L) were calculated. Subgroup analysis was carried out by age. The quality of each study was evaluated according to four criteria: national representativeness, representation of males and females, the sample size, and the sampling protocol. A total of 16 relevant publications were identified, and 8 of these (reporting from 7 unique studies) met our inclusion and exclusion criteria with a total number of 1,699 Qatari subjects. The pooled sample size weighted-average vitamin D concentration (±SD) was 45.3±14.3 nmol/L (95% CI: 44.6-46.0; range 29.2-66.9 nmol/L). The weighted-average prevalence of low vitamin D status was 90.4% (95% CI: 90.1-91.0; range 83%-91%). Age was inversely correlated with vitamin D levels and directly with its insufficiency/deficiency prevalence. There have only been a few studies on the prevalence of low vitamin D in Qatar a very high prevalence of vitamin D insufficiency/deficiency in Qatar that increases with age has been suggested. The present report underlines the need to develop a nationally representative study to further evaluate vitamin D status in Qatar. Given the growing evidence of the role of vitamin D in chronic disease, this study could help develop public health strategies for disease prevention in Qatar.

Inhibition of TIMP1 enhances angiogenesis in vivo and cell migration in vitro.

Neovascular invasion into a 3-dimensional matrix is controlled, in part, by matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). We tested the hypothesis that increasing MMP activity, via a specific blocking antibody to TIMP1, would enhance fibrovascular invasion into a PVA sponge. In vivo, inhibition of TIMP1 doubled the amount of angiogenic invasion (percentage area of invasion 33.5 +/- 3.5 vs 16.9 +/- 9.5, P = 0.003). The blocking antibody to TIMP1 did not increase the proportion of cells that were proliferating in the sponge implants, underscoring the importance of migration. In vitro, human microvascular endothelial cells (hmEC) and dermal fibroblasts treated with the antibody did not secrete greater amounts of collagenase but migrated significantly farther on collagen I (increase in distance migrated 26.6 +/- 9.4%, P = 0.003). Human dermal microvascular endothelial cells exposed to the TIMP1 blocking antibody exhibited a significant change in cell shape to a more elongated morphology. In conclusion, inhibition of TIMP1 increased angiogenesis into a PVA sponge in vivo and enhanced the migration of dermal hmEC and fibroblasts on collagen I in vitro. We propose that blocking TIMP1 improves angiogenesis by increasing cell motility during fibrovascular invasion.

MT1-MMP, but not secreted MMPs, influences the migration of human microvascular endothelial cells in 3-dimensional collagen gels.

Matrix metalloproteinases (MMPs) and their specific inhibitors the TIMPs play significant roles in angiogenesis. We investigated how the expression of specific MMPs and TIMPs by human microvascular endothelial cells (hmECs) was modulated by culture of the cells in 3-dimensional (3D) type I collagen gels versus 2-dimensional (2D) collagen-coated surfaces. By reverse-transcription polymerase chain reaction (RT-PCR), levels of mRNA for MMPs-1, -2, and -13, MT1-MMP, and TIMPs-1 and -2 were similar in 2D versus 3D cultures. By Western blot assay, TIMP-1 and proMMP-1 were present and were expressed similarly in media from 2D versus 3D cultures, whereas active MMPs-1, -9, and -13 were not detected. Active MMP-13 was present in cell lysates (CL) and was increased in lysates from 3D cultures relative to 2D cultures. Relative to 2D cultures, CL and media from 3D cultures exhibited a decrease in expression of TIMP-2 and an increased conversion of proMMP-2 and proMT1-MMP to active or processed forms. The MMP inhibitor GM6001 interfered with the migration of hmECs in 3D cultures, but not in 2D cultures. Addition of active MMP-1 or blocking antibodies to TIMP-1 did not affect the migration of hmECs in 3D collagen. Migration in 3D collagen was decreased by TIMP-2 (an inhibitor of MT1-MMP), but not by TIMP-1 (a poor inhibitor of MT1-MMP, but an efficient inhibitor of MMP-2). Collectively, our data indicate that MT1-MMP contributes significantly to the movement of hmECs through 3D collagen, in contrast to secretory-type MMPs-1, -2, -9, and -13, which are not critical for this movement.