A Comparative Assessment of Non-Laboratory-Based versus Commonly Used Laboratory-Based Cardiovascular Disease Risk Scores in the NHANES III Population

National and international primary CVD risk screening guidelines focus on using total CVD risk scores. Recently, we developed a non-laboratory-based CVD risk score (inputs: age, sex, smoking, diabetes, systolic blood pressure, treatment of hypertension, body-mass index), which can assess risk faster and at lower costs compared to laboratory-based scores (inputs include cholesterol values). We aimed to assess the exchangeability of the non-laboratory-based risk score to four commonly used laboratory-based scores (Framingham CVD [2008, 1991 versions], and Systematic COronary Risk Evaluation [SCORE] for low and high risk settings) in an external validation population.Analyses were based on individual-level, score-specific rankings of risk for adults in the Third National Health and Nutrition Examination Survey (NHANES III) aged 25–74 years, without history of CVD or cancer (n = 5,999). Risk characterization agreement was based on overlap in dichotomous risk characterization (thresholds of 10-year risk >10–20%) and Spearman rank correlation. Risk discrimination was assessed using receiver operator characteristic curve analysis (10-year CVD death outcome). Risk characterization agreement ranged from 91.9–95.7% and 94.2–95.1% with Spearman correlation ranges of 0.957–0.980 and 0.946–0.970 for men and women, respectively. In men, c-statistics for the non-laboratory-based, Framingham (2008, 1991), and SCORE (high, low) functions were 0.782, 0.776, 0.781, 0.785, and 0.785, with p-values for differences relative to the non-laboratory-based score of 0.44, 0.89, 0.68 and 0.65, respectively. In women, the corresponding c-statistics were 0.809, 0.834, 0.821, 0.792, and 0.792, with corresponding p-values of 0.04, 0.34, 0.11 and 0.09, respectively.Every score discriminated risk of CVD death well, and there was high agreement in risk characterization between non-laboratory-based and laboratory-based risk scores, which suggests that the non-laboratory-based score can be a useful proxy for Framingham or SCORE functions in resource-limited settings. Future external validation studies can assess whether the sex-specific risk discrimination results hold in other populations

Linkage Group Selection: Towards Identifying Genes Controlling Strain Specific Protective Immunity in Malaria

Protective immunity against blood infections of malaria is partly specific to the genotype, or strain, of the parasites. The target antigens of Strain Specific Protective Immunity are expected, therefore, to be antigenically and genetically distinct in different lines of parasite. Here we describe the use of a genetic approach, Linkage Group Selection, to locate the target(s) of Strain Specific Protective Immunity in the rodent malaria parasite Plasmodium chabaudi chabaudi. In a previous such analysis using the progeny of a genetic cross between P. c. chabaudi lines AS-pyr1 and CB, a location on P. c. chabaudi chromosome 8 containing the gene for merozoite surface protein-1, a known candidate antigen for Strain Specific Protective Immunity, was strongly selected. P. c. chabaudi apical membrane antigen-1, another candidate for Strain Specific Protective Immunity, could not have been evaluated in this cross as AS-pyr1 and CB are identical within the cell surface domain of this protein. Here we use Linkage Group Selection analysis of Strain Specific Protective Immunity in a cross between P. c. chabaudi lines CB-pyr10 and AJ, in which merozoite surface protein-1 and apical membrane antigen-1 are both genetically distinct. In this analysis strain specific immune selection acted strongly on the region of P. c. chabaudi chromosome 8 encoding merozoite surface protein-1 and, less strongly, on the P. c. chabaudi chromosome 9 region encoding apical membrane antigen-1. The evidence from these two independent studies indicates that Strain Specific Protective Immunity in P. c. chabaudi in mice is mainly determined by a narrow region of the P. c. chabaudi genome containing the gene for the P. c. chabaudi merozoite surface protein-1 protein. Other regions, including that containing the gene for P. c. chabaudi apical membrane antigen-1, may be more weakly associated with Strain Specific Protective Immunity in these parasites

Failure to detect Plasmodium vivax in West and Central Africa by PCR species typing

<p>Abstract</p> <p>Background</p> <p><it>Plasmodium vivax </it>is estimated to affect 75 million people annually. It is reportedly absent, however, from west and central Africa due to the high prevalence of the Duffy negative phenotype in the indigenous populations. Despite this, non-African travellers consistently return to their own countries with <it>P. vivax </it>malaria after visiting this region. An attempt was made, therefore, to detect the presence of <it>P. vivax </it>parasites in blood samples collected from the indigenous populations of west and central Africa.</p> <p>Methods</p> <p>Parasite species typing (for all four human malaria parasites) was carried out by PCR on 2,588 blood samples collected from individuals from nine African malaria-endemic countries.</p> <p>Results</p> <p>Most infections (98.5%) were <it>Plasmodium falciparum</it>, <it>Plasmodium malariae </it>was identified in 8.5% of all infections, and <it>Plasmodium ovale </it>in 3.9%. The prevalence of both parasites varied greatly by country. Only one case of <it>P. vivax </it>was detected from Sao Tome, an island off the west coast of Africa, confirming the scarcity of this parasite in Africa.</p> <p>Conclusion</p> <p>The prevalence of <it>P. vivax </it>in local populations in sub-Saharan Africa is very low, despite the frequent identification of this parasite in non-African travellers.</p

Pre-hospital ECG for acute coronary syndrome in urban India: A cost-effectiveness analysis

<p>Abstract</p> <p>Background</p> <p>Patients with acute coronary syndrome (ACS) in India have increased pre-hospital delay and low rates of thrombolytic reperfusion. Use of ECG could reduce pre-hospital delay among patients who first present to a general practitioner (GP). We assessed whether performing ECG on patients with acute chest pain would improve long-term outcomes and be cost-effective.</p> <p>Methods</p> <p>We created a Markov model of urban Indian patients presenting to a GP with acute chest pain to compare a GP's performing an ECG versus not performing one. Variables describing the accuracy of a GP's referral decision in chest pain and ACS, ACS treatment patterns, the effectiveness of thrombolytic reperfusion, and costs were derived from Indian data where available and other developed world studies. The model was used to estimate the incremental cost-effectiveness ratio (ICER) of the intervention in 2007 US dollars per quality adjusted life years (QALY) gained.</p> <p>Results</p> <p>Under baseline assumptions, the ECG strategy cost an additional $12.65 per QALY gained compared to no ECG. Sensitivity analyses around the cost of the ECG, cost of thrombolytic, and referral accuracy of the GP yielded ICERs for the ECG strategy ranging between cost-saving and$1124/QALY. All results indicated the intervention is cost-effective under current World Health Organization recommendations.</p> <p>Conclusions</p> <p>While direct presentation to the hospital with acute chest pain is preferable, in urban Indian patients presenting first to a GP, an ECG performed by the GP is a cost-effective strategy to reduce disability and mortality. This strategy should be clinically studied and considered until improved emergency transport services are available.</p

Upregulated Genes In Sporadic, Idiopathic Pulmonary Arterial Hypertension

BACKGROUND: To elucidate further the pathogenesis of sporadic, idiopathic pulmonary arterial hypertension (IPAH) and identify potential therapeutic avenues, differential gene expression in IPAH was examined by suppression subtractive hybridisation (SSH). METHODS: Peripheral lung samples were obtained immediately after removal from patients undergoing lung transplant for IPAH without familial disease, and control tissues consisted of similarly sampled pieces of donor lungs not utilised during transplantation. Pools of lung mRNA from IPAH cases containing plexiform lesions and normal donor lungs were used to generate the tester and driver cDNA libraries, respectively. A subtracted IPAH cDNA library was made by SSH. Clones isolated from this subtracted library were examined for up regulated expression in IPAH using dot blot arrays of positive colony PCR products using both pooled cDNA libraries as probes. Clones verified as being upregulated were sequenced. For two genes the increase in expression was verified by northern blotting and data analysed using Student's unpaired two-tailed t-test. RESULTS: We present preliminary findings concerning candidate genes upregulated in IPAH. Twenty-seven upregulated genes were identified out of 192 clones examined. Upregulation in individual cases of IPAH was shown by northern blot for tissue inhibitor of metalloproteinase-3 and decorin (P < 0.01) compared with the housekeeping gene glyceraldehydes-3-phosphate dehydrogenase. CONCLUSION: Four of the up regulated genes, magic roundabout, hevin, thrombomodulin and sucrose non-fermenting protein-related kinase-1 are expressed specifically by endothelial cells and one, muscleblind-1, by muscle cells, suggesting that they may be associated with plexiform lesions and hypertrophic arterial wall remodelling, respectively

Losartan Slows Pancreatic Tumor Progression and Extends Survival of SPARC-Null Mice by Abrogating Aberrant TGFβ Activation

Pancreatic adenocarcinoma, a desmoplastic disease, is the fourth leading cause of cancer-related death in the Western world due, in large part, to locally invasive primary tumor growth and ensuing metastasis. SPARC is a matricellular protein that governs extracellular matrix (ECM) deposition and maturation during tissue remodeling, particularly, during wound healing and tumorigenesis. In the present study, we sought to determine the mechanism by which lack of host SPARC alters the tumor microenvironment and enhances invasion and metastasis of an orthotopic model of pancreatic cancer. We identified that levels of active TGFβ1 were increased significantly in tumors grown in SPARC-null mice. TGFβ1 contributes to many aspects of tumor development including metastasis, endothelial cell permeability, inflammation and fibrosis, all of which are altered in the absence of stromal-derived SPARC. Given these results, we performed a survival study to assess the contribution of increased TGFβ1 activity to tumor progression in SPARC-null mice using losartan, an angiotensin II type 1 receptor antagonist that diminishes TGFβ1 expression and activation in vivo. Tumors grown in SPARC-null mice progressed more quickly than those grown in wild-type littermates leading to a significant reduction in median survival. However, median survival of SPARC-null animals treated with losartan was extended to that of losartan-treated wild-type controls. In addition, losartan abrogated TGFβ induced gene expression, reduced local invasion and metastasis, decreased vascular permeability and altered the immune profile of tumors grown in SPARC-null mice. These data support the concept that aberrant TGFβ1-activation in the absence of host SPARC contributes significantly to tumor progression and suggests that SPARC, by controlling ECM deposition and maturation, can regulate TGFβ availability and activation

SPARC: a matricellular regulator of tumorigenesis

Although many clinical studies have found a correlation of SPARC expression with malignant progression and patient survival, the mechanisms for SPARC function in tumorigenesis and metastasis remain elusive. The activity of SPARC is context- and cell-type-dependent, which is highlighted by the fact that SPARC has shown seemingly contradictory effects on tumor progression in both clinical correlative studies and in animal models. The capacity of SPARC to dictate tumorigenic phenotype has been attributed to its effects on the bioavailability and signaling of integrins and growth factors/chemokines. These molecular pathways contribute to many physiological events affecting malignant progression, including extracellular matrix remodeling, angiogenesis, immune modulation and metastasis. Given that SPARC is credited with such varied activities, this review presents a comprehensive account of the divergent effects of SPARC in human cancers and mouse models, as well as a description of the potential mechanisms by which SPARC mediates these effects. We aim to provide insight into how a matricellular protein such as SPARC might generate paradoxical, yet relevant, tumor outcomes in order to unify an apparently incongruent collection of scientific literature