Additive effect of LRP8/APOER2 R952Q variant to APOE ε2/ε3/ε4 genotype in modulating apolipoprotein E concentration and the risk of myocardial infarction: a case-control study

BACKGROUND: The R952Q variant in the low density lipoprotein receptor-related protein 8 (LRP8)/apolipoprotein E receptor 2 (ApoER2) gene has been recently associated with familial and premature myocardial infarction (MI) by means of genome-wide linkage scan/association studies. We were interested in the possible interaction of the R952Q variant with another established cardiovascular genetic risk factor belonging to the same pathway, namely apolipoprotein E (APOE) epsilon2/epsilon3/epsilon4 genotype, in modulating apolipoprotein E (ApoE) plasma levels and risk of MI. METHODS: In the Italian cohort used to confirm the association of the R952Q variant with MI, we assessed lipid profile, apolipoprotein concentrations, and APOE epsilon2/epsilon3/epsilon4 genotype. Complete data were available for a total of 681 subjects in a case-control setting (287 controls and 394 patients with MI). RESULTS: Plasma ApoE levels decreased progressively across R952Q genotypes (mean levels +/- SD = RR: 0.045 +/- 0.020, RQ: 0.044 +/- 0.014, QQ: 0.040 +/- 0.008 g/l; P for trend = 0.047). Combination with APOE genotypes revealed an additive effect on ApoE levels, with the highest level observed in RR/non-carriers of the E4 allele (0.046 +/- 0.021 g/l), and the lowest level in QQ/E4 carriers (0.035 +/- 0.009 g/l; P for trend = 0.010). QQ/E4 was also the combined genotype with the most significant association with MI (OR 3.88 with 95\%CI 1.08-13.9 as compared with RR/non-carriers E4). CONCLUSION: Our data suggest that LRP8 R952Q variant may have an additive effect to APOE epsilon2/epsilon3/epsilon4 genotype in determining ApoE concentrations and risk of MI in an Italian population

Cancer survival in England and Wales at the end of the 20th century

Survival has risen steadily since the 1970s for most cancers in adults in England and Wales, but persistent inequalities exist between those living in affluent and deprived areas. These differences are not seen for children. For many of the common adult cancers, these inequalities in survival (the 'deprivation gap') became more marked in the 1990s. This volume presents extended analyses of survival for adults diagnosed during the 14 years 1986-1999 and followed up to 2001, including trends in overall survival in England and Wales and trends in the deprivation gap in survival. The analyses include individual tumour data for 2.2 million cancer patients. This article outlines the structure of the supplement - an article for each of the 20 most common cancers in adults, followed by an expert commentary from one of the leading UK clinicians specialising in malignancies of that organ or system. The available data, quality control and methods of analysis are described here, rather than repeated in each of the 20 articles. We open the discussion between clinicians and epidemiologists on how to interpret the observed trends and inequalities in cancer survival, and we highlight some of the most important contrasts in these very different points of view. Survival improved substantially for adult cancer patients in England and Wales up to the end of the 20th century. Although socioeconomic inequalities in survival are remarkably persistent, the overall patterns suggest that these inequalities are largely avoidable

Znf202 Affects High Density Lipoprotein Cholesterol Levels and Promotes Hepatosteatosis in Hyperlipidemic Mice

Background: The zinc finger protein Znf202 is a transcriptional suppressor of lipid related genes and has been linked to hypoalphalipoproteinemia. A functional role of Znf202 in lipid metabolism in vivo still remains to be established. Methodology and Principal Findings: We generated mouse Znf202 expression vectors, the functionality of which was established in several in vitro systems. Next, effects of adenoviral znf202 overexpression in vivo were determined in normo- as well as hyperlipidemic mouse models. Znf202 overexpression in mouse hepatoma cells mhAT3F2 resulted in downregulation of members of the Apoe/c1/c2 and Apoa1/c3/a4 gene cluster. The repressive activity of Znf202 was firmly confirmed in an apoE reporter assay and Znf202 responsive elements within the ApoE promoter were identified. Adenoviral Znf202 transfer to Ldlr-/- mice resulted in downregulation of apoe, apoc1, apoa1, and apoc3 within 24 h after gene transfer. Interestingly, key genes in bile flux (abcg5/8 and bsep) and in bile acid synthesis (cyp7a1) were also downregulated. At 5 days post-infection, the expression of the aforementioned genes was normalized, but mice had developed severe hepatosteatosis accompanied by hypercholesterolemia and hypoalphalipoproteinemia. A much milder phenotype was observed in wildtype mice after 5 days of hepatic Znf202 overexpression. Interestingly and similar to Ldl-/- mice, HDL-cholesterol levels in wildtype mice were lowered after hepatic Znf202 overexpression. Conclusion/Significance: Znf202 overexpression in vivo reveals an important role of this transcriptional regulator in liver lipid homeostasis, while firmly establishing the proposed key role in the control of HDL levels

Hyper-IgG4 disease: report and characterisation of a new disease

BACKGROUND: We highlight a chronic inflammatory disease we call 'hyper-IgG4 disease', which has many synonyms depending on the organ involved, the country of origin and the year of the report. It is characterized histologically by a lymphoplasmacytic inflammation with IgG4-positive cells and exuberant fibrosis, which leaves dense fibrosis on resolution. A typical example is idiopathic retroperitoneal fibrosis, but the initial report in 2001 was of sclerosing pancreatitis. METHODS: We report an index case with fever and severe systemic disease. We have also reviewed the histology of 11 further patients with idiopathic retroperitoneal fibrosis for evidence of IgG4-expressing plasma cells, and examined a wide range of other inflammatory conditions and fibrotic diseases as organ-specific controls. We have reviewed the published literature for disease associations with idiopathic, systemic fibrosing conditions and the synonyms: pseudotumour, myofibroblastic tumour, plasma cell granuloma, systemic fibrosis, xanthofibrogranulomatosis, and multifocal fibrosclerosis. RESULTS: Histology from all 12 patients showed, to varying degrees, fibrosis, intense inflammatory cell infiltration with lymphocytes, plasma cells, scattered neutrophils, and sometimes eosinophilic aggregates, with venulitis and obliterative arteritis. The majority of lymphocytes were T cells that expressed CD8 and CD4, with scattered B-cell-rich small lymphoid follicles. In all cases, there was a significant increase in IgG4-positive plasma cells compared with controls. In two cases, biopsies before and after steroid treatment were available, and only scattered plasma cells were seen after treatment, none of them expressing IgG4. Review of the literature shows that although pathology commonly appears confined to one organ, patients can have systemic symptoms and fever. In the active period, there is an acute phase response with a high serum concentration of IgG, and during this phase, there is a rapid clinical response to glucocorticoid steroid treatment. CONCLUSION: We believe that hyper-IgG4 disease is an important condition to recognise, as the diagnosis can be readily verified and the outcome with treatment is very good

Evaluation of hypertension and proteinuria as markers of efficacy in anti-angiogenic therapy for metastatic colorectal cancer.

BACKGROUND: The vascular endothelial growth factor pathway is strongly implicated in cancer-related angiogenesis. Antiangiogenic agents such as bevacizumab commonly cause hypertension (HTN) and proteinuria (PTN), which may be biomarkers of response and clinical outcome.STUDY: We conducted a retrospective analysis of patients with histologically proven metastatic colorectal cancer (mCRC) treated with either bevacizumab or a tyrosine kinase inhibitor in combination with chemotherapy at The Christie Hospital from January 2006 to September 2009.RESULTS: Of 90 patients evaluated, 50 were eligible. Seventeen (34%), 4 (8%), and 3 (6%) patients developed Common Toxicity Criteria (v 3.0) grades 1, 2, and 3 HTN, respectively. Response rates were 42% for patients with grades 0 to 1 HTN compared with 86% for patients with ≥grade 2 HTN (P=0.043). Median overall survival was 21.6 months for patients with grades 0 to 1 HTN and 25.2 months for patients with ≥grade 2 HTN (P=0.270). Twelve patients (24%) developed grade 1 PTN and 4 patients (8%) developed ≥grade 2 PTN. Median overall survival was 23.9 months for patients with grades 0 to 1 PTN and 4.2 months for those with ≥grade 2 PTN (P=0.028).CONCLUSIONS: To our knowledge, this is the first study to demonstrate the utility of PTN as a surrogate marker of outcome in antiangiogenic therapy for metastatic colorectal cancer. Although HTN is predictive of a significantly higher response rate, the development of PTN during treatment with bevacizumab or tyrosine kinase inhibitor portends poorer survival and should be evaluated prospectively.</p

Longitudinal analysis of thoracic aortic expansion in non-syndromic real-world patients

Remodeling of the thoracic aorta is commonly seen and viewed as a precursor to an aortic aneurysm. However, while aneurysms have been shown to expand at a rate of approximately 1 mm annually, the expansion of the pre-aneurysmal aorta is poorly characterized, especially in relation to age, gender, and aortic size per se. We identified patients that had undergone echocardiography at least twice at a large university medical center. Diagnosis codes, medications, and blood test results were obtained from hospital records. Syndromic patients were excluded (e.g., Marfan's syndrome, bicuspid aortic valve). Final population comprised n = 24,928 patients (median age 61.2 years (inter-quartile range (IQR): 50.6–71.5); 55.8% males) that had undergone a median of 3 echocardiograms (2–4; range 2–27) during a median of 4.0 years (IQR: 2.3–6.2). Hypertension was present in 39.6% of patients and diabetes in 20.7%, median LV ejection fraction was 56.0% (IQR: 41.0–62.0). Aortic size measurements were analyzed in mixed models while clustering on individual patients. Mean expansion was determined for sinus of Valsalva as 1.93 (95% confidence interval; CI95: 1.87–1.99) mm per decade, and for ascending aorta as 1.76 (CI95: 1.70–1.82) mm per decade. Faster expansion was found in males, with larger aortic size, and younger age (p for interaction <0.05 for all). In conclusion, expansion of the thoracic aorta, in real world, non-syndromic patients, is slow and averages <2 mm per decade. This will help to inform management of this large patient group