SCIENTIFIC RATIONALE. 5. 1 Novel HDL-C raising therapies There are different proposed mechanisms for the HDL-C protective role; reverse cholesterol transport, the process of transporting excess cholesterol from the arterial wall’s foam macro- phages to the liver, bile, and feces is one of HDL’s anti-atherogenic properties79, 80. Furthermore, HDL’s anti-oxidative activity further protects against atherosclerosis81, 82. In the endothelium, nitric oxide protects against inflammation, HDL promotes vasoprotection by enhancing nitric oxide synthase and thereby increasing the production of nitric oxide83, 84. In addition to protec- tion against platelet activation through endothelial protection, HDL inhibits the coagulation cascade through serine protease protein C, which inactivates factors Va and VIIa83. Circulating HDL particles are very heterogeneous with a very complex metabolic profile. There are three subclasses of HDL which vary in quantitative and qualitative content of lipids; discoid HDL particles (lipid-free HDL or apolipoprotein A-1) which mediates reverse cholesterol transport; further esterification of these HDL particles generates the other two subclasses; HDL2 and HDL3 which are spherical HDL particles. These mature HDL particles may induce further cholesterol efflux. Smaller HDL3 particles may more efficiently promote cholesterol efflux79, 85. Thus it appears that the subtype of HDL seems to matter. The next few years should provide answers to whether we should target raising specific HDL subclasses rather than HDL-C itself. Structural and functional changes accompany HDL in the setting of acute or chronic inflam- mation, CHD or type 2 diabetes mellitus. These changes are induced by leukocyte myelo- peroxidase which may alter the function of the normally atheroprotective anti-inflammatory HDL molecules into the so-called dysfunctional HDL with pro-inflammatory properties. This results in reduced efficacy of reverse cholesterol transport, and the ability of HDL to counter- act the inhibitory effect of oxidized LDL on vascular relaxation86, 87.
SCIENTIFIC RATIONALE. Host serum protein biomarkers that indicate a high likelihood for active TB disease represent attractive targets for integration into screening tests. The EDCTP 1-funded African European Tuberculosis Consortium (AE-TBC) has previously investigated host biosignatures in whole blood culture supernatants after overnight stimulation with Mycobacterium tuberculosis (MTB) specific proteins. During this project >1,300 people from high TB prevalence areas (South Africa, Namibia, Malawi, The Gambia, Uganda and Ethiopia) with symptoms suggestive of active TB were recruited and worked up diagnostically with CXR, sputum culture, smear and GeneXpert. One third of the participants had confirmed active TB and 26% were HIV co-infected. A no-go decision was taken regarding the whole blood MTB stimulated culture signature as low sensitivity (75 - 80%) with specificity of 86% was deemed insufficient for further development and as an overnight assay is not suitable for rapid point of care (POC) testing. However, a promising serum host inflammatory signature was identified during this project after investigation of more than 70 serum host inflammation markers, including acute phase proteins, T helper cell 1, T helper cell 2 and regulatory cytokines, soluble cytokine receptors and growth factors. The original set of markers for screening were chosen according to the availability of multiplexed assays (Luminex platform) and their known roles in inflammation and represented a wide spectrum of markers with diagnostic potential. The most promising host serum protein signature was subsequently validated on 687 people from five African countries with suspected TB, regardless of HIV infection status or ethnicity, providing the basis for the follow-up work suggested herein. The six-analyte signature of C-reactive protein (CRP), Interferon gamma (IFN-γ), pre-albumin, complement factor H (CFH), apolipoprotein A1 and inducible protein 10 (IP-10) ascertained TB disease with a sensitivity of 89% (CI 78 – 95%) and specificity of 76% (CI 68 – 83%), (positive predictive value of 61%; negative predictive value of 94%) ([7], [8]). Measurement of multiple markers and evaluation of their ratios offset a lack of disease specificity of individual markers. These performance characteristics would constitute a valuable screening test if converted into an inexpensive POC test and would prioritize individuals with a high likelihood of active TB for confirmatory testing by GeneXpert. During the AE-TBC pro...
SCIENTIFIC RATIONALE. During my 2012 practicum in the Surveillance Department in KSA, I noticed an increase in the number of dengue fever cases in Makkah City, especially among children. In one Makkah study, 24% of the cases occurred among children < 12 years of age [10]. Also, two of my relatives were diagnosed with dengue fever; they were admitted to the hospital. The cost of their care was very high. In addition, the number of cases in the general population continues to increase, even while the MOH invests an enormous amount of money for health education and vector control. To reduce the number of dengue infections in Makkah, the KSA MOH must work to improve and enforce its prevention measures through multiple levels. To do this, it is very important to first understand the changing distribution of dengue infection over time and to identify high-risk groups. This epidemiologic information helps guide the development of proper policies. Dengue fever is a reportable condition and case-based information is collected by the VBDU in the KSA MOH. However, these case records have not been analyzed beyond the production of yearly aggregated reports. Therefore, I analyzed the dengue fever data in Makkah collected by the VBDU from 2008 to 2012 to inform policymakers about any conspicuous trends or at-risk population subgroups.
