Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes : Rationale and design of the global EAS Familial Hypercholesterolaemia Studies Collaboration

Background: The potential for global collaborations to better inform public health policy regarding major non-hypercholesterolaemia (FH), a common genetic disorder associated with premature cardiovascular disease, is yet to be reliably ascertained using similar approaches. The European Atherosclerosis Society FH Studies Collaboration (EAS FHSC) is a new initiative of international stakeholders which will help establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide. Methods: The EAS FHSC will maximise the potential exploitation of currently available and future FH data (retrospective and prospective) by bringing together regional/national/international data sources with access to individuals with a clinical and/or genetic diagnosis of heterozygous or homozygous FH. A novel bespoke electronic platform and FH Data Warehouse will be developed to allow secure data sharing, validation, cleaning, pooling, harmonisation and analysis irrespective of the source or format. Standard statistical procedures will allow us to investigate cross-sectional associations, patterns of real-world practice, trends over time, and analyse risk and outcomes (e.g. cardiovascular outcomes, all-cause death), accounting for potential confounders and subgroup effects. Conclusions: The EAS FHSC represents an excellent opportunity to integrate individual efforts across the world to tackle the global burden of FH. The information garnered from the registry will help reduce gaps in knowledge, inform best practices, assist in clinical trials design, support clinical guidelines and policies development, and ultimately improve the care of FH patients. (C) 2016 Elsevier Ireland Ltd.Peer reviewe

Designing organisational effectiveness in social entrepreneurial enterprises

Background: Fundamental principles that encourage problem solving are included in the intersection between design thinking and systems thinking. In this study, we examined if these principles contribute to the nature of organisational effectiveness (OE) in the context of a social enterprise. Aim: The objective of the study was to explore the nature of OE in social enterprises. Setting: This exploratory qualitative study investigated the OE of social enterprises in South Africa. Methods: A three-phased Delphi method was conducted by a panel of experts. Results: Our findings indicate that the principles for the OE of social enterprises include, in particular, good, just, and useful services and/or products, as well as a satisfying human experience. In the context of a social enterprise, OE is therefore about the mission and resources of the enterprise. The enterprise can be viewed as making an impact when satisfying human (community and/or beneficiary) needs through useful products or services designed for good, and when promoting just relationships among and ethical conduct by all stakeholders. Conclusion: The framework or principles for social enterprises’ OE may be used to guide leadership, governance of resources (such as finances), and training in solving ‘wicked problems’ in such ecosystems. It is recommended that social entrepreneurs also apply the framework. Contribution: This paper offers four principles that are applicable when systems thinking overlaps with design thinking to guide the OE of social enterprises

Effects of Eprosartan on Serum Metabolic Parameters in Patients with Essential Hypertension

The effect of the anti-hypertensive drug eprosartan on metabolic parameters is currently not extensively documented. We evaluated the effect of eprosartan on parameters involved in atherogenesis, oxidative stress and clotting activity. This open-label unblinded intervention study included 40 adult patients with essential hypertension taking eprosartan. Eprosartan significantly reduced by 8% (p<0.001) the systolic and by 13% (p<.001) the diastolic blood pressure, and in-creased by 24% the time needed to produce oxidative by-products (p=0.001), a marker of oxidative stress. In contrast, ep-rosartan did not alter 8-isoprostane (8-epiPGF2a) levels, another marker of oxidative stress. Additionally, eprosartan re-duced by 14% aspartate aminotransferase and by 21% then alanine aminotransferase activity, while it had a neutral effect on the lipid profile and apolipoprotein levels and did not influence glucose homeostasis, creatinine and uric acid levels. Eprosartan did not affect the clotting/fibrinolytic status (estimated by plasminogen activator inhibitor 1, tissue plasmino-gen activator and a2 antiplasmin levels), or the enzymatic activity of the lipoprotein associated phospholipase A2 (Lp-PLA2) and paraoxonase 1 (PON1). In conclusion, eprosartan should be mainly considered as an anti-hypertensive agent with neutral effects on most of the metabolic parameters in hypertensive patients

The chelation of colonic luminal iron by a unique sodium alginate for the improvement of gastrointestinal health

Scope: Iron is an essential nutrient. However, in animal models, excess unabsorbed dietary iron residing within the colonic lumen has been shown to exacerbate inflammatory bowel disease and intestinal cancer. Therefore, the aims of this study were to screen a panel of alginates to identify a therapeutic that can chelate this pool of iron and thus be beneficial for intestinal health. Methods and results: Using several in vitro intestinal models, it is evident that only one alginate (Manucol LD) of the panel tested was able to inhibit intracellular iron accumulation as assessed by iron-mediated ferritin induction, transferrin receptor expression, intracellular 59Fe concentrations, and iron flux across a Caco-2 monolayer. Additionally, Manucol LD suppressed iron absorption in mice, which was associated with increased fecal iron levels indicating iron chelation within the gastrointestinal tract. Furthermore, the bioactivity of Manucol LD was found to be highly dependent on both its molecular weight and its unique compositional sequence. Conclusion: Manucol LD could be useful for the chelation of this detrimental pool of unabsorbed iron and it could be fortified in foods to enhance intestinal health.</p

Effect of Plant Polyphenols on Adipokine Secretion from Human SGBS Adipocytes

Introduction. Adipose tissue contributes to atherosclerosis with mechanisms related to adipokine secretion. Polyphenols may exhibit antiatherogenic properties. The aim of the study was to investigate the effects of three polyphenols, namely, quercetin, epigallocatechin gallate (EGCG), and resveratrol on adipokine secretion from cultured human adipocytes. Methods. Human SGBS adipocytes were treated with quercetin, EGCG, and resveratrol for 24 and 48 hours. Visfatin, leptin, and adiponectin were measured in the supernatant. Results. Visfatin secretion was inhibited by quercetin 10 muM by 16% and 24% at 24 and 48 hours respectively. The corresponding changes for quercetin 25 muM were 47% and 48%. Resveratrol 25 muM reduced visfatin by 28% and 38% at 24 and 48 hours. EGCG did not have an effect on visfatin. None of tested polyphenols influenced leptin and adiponectin secretion. Conclusion. Quercetin and resveratrol significantly decreased visfatin secretion from SGBS adipocytes. This effect may contribute to their overall antiatherogenic properties.Biochem Res In

LDL cholesterol estimation in patients with the metabolic syndrome

BACKGROUND: The Friedewald formula (LDL-F) for the estimation of low-density lipoprotein (LDL) cholesterol concentrations is the most often used formula in clinical trials and clinical practice. However, much concern has been raised as to whether this formula is applicable in all patient populations such as the presence of chylomicronaemia and/or hypertriglyceridaemia. The aim of the present study was to evaluate various LDL cholesterol calculation formulas as well as LDL cholesterol levels provided by the Lipoprint LDL System (LDL-L) in patients with the metabolic syndrome (MetSyn). RESULTS: LDL-F showed significant differences from other formulas in the total cohort, as well as in MetSyn individuals. This was not the case in nonMetSyn subjects, where LDL-F did not differ with other formulas, with the exception of one formula (LDL by Planella, LDL-P). The bias between LDL-F and other LDL estimation formulas were significantly higher in MetSyn subjects compared to nonMetSyn individuals, except for LDL-L which produced similar bias with LDL-F in both study groups. CONCLUSION: LDL-F seems to exhibit some limitations as far as the calculation of LDL-C levels in patients with the MetSyn is concerned. LDL-L might be more accurate in MetSyn subjects, but so far its use is limited for the estimation of small, dense LDL (sdLDL) cholesterol levels and mean LDL particle size for research purposes only.Lipids Health Di

Desmocollin switching in colorectal cancer

The desmocollins are members of the desmosomal cadherin family of cell–cell adhesion molecules. They are essential constituents of desmosomes, intercellular junctions that play a critical role in the maintenance of tissue integrity in epithelia and cardiac muscle. In humans, three desmocollins (Dsc1, Dsc2 and Dsc3) have been described. The desmocollins exhibit tissue-specific patterns of expression; only Dsc2 is expressed in normal colonic epithelium. We have found switching between desmocollins in sporadic colorectal adenocarcinoma with a reduction in Dsc2 protein (in 8/16 samples analysed by immunohistochemistry) being accompanied by de novo expression of Dsc1 (16/16) and Dsc3 (7/16). Similar results were obtained by western blotting of a further 16 samples. No change was found in Dsc2 mRNA, but de novo expression of Dscs 1 and 3 was accompanied by increased message levels. Loss of Dsc2 (8/19) and de novo expression of Dsc1 (11/19) and Dsc3 (6/19) was also found in colorectal adenocarcinomas on a background of colitis. The data raise the possibility that switching of desmocollins could play an important role in the development of colorectal cancer

Oesophageal adenocarcinoma is associated with a deregulation in the MYC/MAX/MAD network

Oesophageal adenocarcinoma, which arises from an acquired columnar lesion, Barrett's metaplasia, is rising in incidence more rapidly than any other cancer in the Western world. Elevated expression of c-MYC has been demonstrated in oesophageal adenocarcinoma; however, the expression of other members of the MYC/MAX/MAD network has not been addressed. The aims of this work were to characterise the expression of c-MYC, MAX and the MAD family in adenocarcinoma development and assess the effects of overexpression on cellular behaviour. mRNA expression in samples of Barrett's metaplasia and oesophageal adenocarcinoma were examined by qRT–PCR. Semi-quantitative immunohistochemistry and western blotting were used to examine cellular localisation and protein levels. Cellular proliferation and mRNA expression were determined in SEG1 cells overexpressing c-MYCER or MAD1 using a bromodeoxyuridine assay and qRT–PCR, respectively. Consistent with previous work expression of c-MYC was deregulated in oesophageal adenocarcinoma. Paradoxically, increased expression of putative c-MYC antagonists MAD1 and MXI1 was observed in tumour specimens. Overexpression of c-MYC and MAD proteins in SEG1 cells resulted in differential expression of MYC/MAX/MAD network members and reciprocal changes in proliferation. In conclusion, the expression patterns of c-MYC, MAX and the MAD family were shown to be deregulated in the oesophageal cancer model

A Genetic Biomarker of Oxidative Stress, the Paraoxonase-1 Q192R Gene Variant, Associates with Cardiomyopathy in CKD: A Longitudinal Study

Background. Oxidative stress is a hallmark of CKD and this alteration is strongly implicated in LV hypertrophy and in LV dysfunction. Methods and Patients. We resorted to the strongest genetic biomarker of paraoxonase-1 (PON1) activity, the Q192R variant in the PON1 gene, to unbiasedly assess (Mendelian randomization) the cross-sectional and longitudinal association of this gene-variant with LV mass and function in 206 CKD patients with a 3-year follow-up. Results. The R allele of Q192R polymorphism associated with oxidative stress as assessed by plasma 8-isoPGF2α (P=0.03) and was dose-dependently related in a direct fashion to LVMI (QQ: 131.4 ± 42.6 g/m2; RQ: 147.7 ± 51.1 g/m2; RR: 167.3 ± 41.9 g/m2; P=0.001) and in an inverse fashion to systolic function (LV Ejection Fraction) (QQ: 79 ± 12%; RQ: 69 ± 9%; RR: 65 ± 10% P=0.002). On longitudinal observation, this gene variant associated with the evolution of the same echocardiographic indicators [LVMI: 13.40 g/m2 per risk allele, P=0.005; LVEF: −2.96% per risk allele, P=0.001]. Multivariate analyses did not modify these associations. Conclusion. In CKD patients, the R allele of the Q192R variant in the PON1 gene is dose-dependently related to the severity of LVH and LV dysfunction and associates with the longitudinal evolution of these cardiac alterations. These results are compatible with the hypothesis that oxidative stress is implicated in cardiomyopathy in CKD patients

The impact of pre‐operative intravenous iron on quality of life after colorectal cancer surgery: outcomes from the intravenous iron in colorectal cancer‐associated anaemia (IVICA) trial

Anaemia is associated with a reduction in quality of life, and is common in patients with colorectal cancer . Werecently reported thefindings of the intravenous iron in colorectal cancer-associated anaemia (IVICA) trialcomparing haemoglobin levels and transfusion requirements following intravenous or oral iron replacement inanaemic colorectal cancer patients undergoing elective surgery. In this follow-up study, we compared theefficacy of intravenous and oral iron at improving quality of life in this patient group. We conducted amulticentre, open-label randomised controlled trial. Anaemic colorectal cancer patients were randomlyallocated at least two weeks pre-operatively, to receive either oral (ferrous sulphate) or intravenous (ferriccarboxymaltose) iron. We assessed haemoglobin and quality of life scores at recruitment, immediately beforesurgery and at outpatient review approximately three months postoperatively, using the Short Form 36,EuroQoL 5-dimension 5-level and Functional Assessment of Cancer Therapy–Anaemia questionnaires. Werecruited 116 anaemic patients across seven UK centres (oral iron n=61 (53%), and intravenous iron n=55(47%)). Eleven quality of life components increased by a clinically significant margin in the intravenous irongroup between recruitment and surgery compared with one component for oral iron. Median (IQR [range])visual analogue scores were significantly higher with intravenous iron at a three month outpatient review (oraliron 70, (60–85 [20–95]); intravenous iron 90 (80–90 [50–100]), p=0.001). The Functional Assessment ofCancer Therapy–Anaemia score comprises of subscales related to cancer, fatigue and non-fatigue itemsrelevant to anaemia. Median outpatient scores were higher, and hence favourable, for intravenous iron on theFunctional Assessment of Cancer Therapy–Anaemia subscale (oral iron 66 (55–72 [23–80]); intravenous iron 71(66–77 [46–80]); p=0.002), Functional Assessment of Cancer Therapy–Anaemia trial outcome index (oral iron108 (90–123 [35–135]); intravenous iron 121 (113–124 [81–135]); p=0.003) and Functional Assessment ofCancer Therapy–Anaemia total score (oral iron 151 (132–170 [69–183]); intravenous iron 168 (160–174 [125–186]); p=0.005). Thesefindings indicate that intravenous iron is more efficacious at improving quality of lifescores than oral iron in anaemic colorectal cancer patients