Replication of LDL SWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses

<p><b>Background:</b> The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly.</p> <p><b>Methods:</b> The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification.</p> <p><b>Results:</b> Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results.</p> <p><b>Conclusion:</b> With the GWAS in the PROSPER/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof-of-principle study we show that the PROSPER/PHASE study can be used to investigate genetic associations in a similar way to population based studies. The next step of the PROSPER/PHASE study is to identify the genetic variation responsible for the variation in LDL-cholesterol lowering in response to statin treatment in collaboration with other large trials.</p&gt

Multilayer metamaterial absorbers inspired by perfectly matched layers

We derive periodic multilayer absorbers with effective uniaxial properties similar to perfectly matched layers (PML). This approximate representation of PML is based on the effective medium theory and we call it an effective medium PML (EM-PML). We compare the spatial reflection spectrum of the layered absorbers to that of a PML material and demonstrate that after neglecting gain and magnetic properties, the absorber remains functional. This opens a route to create electromagnetic absorbers for real and not only numerical applications and as an example we introduce a layered absorber for the wavelength of $8$~$\mu$m made of SiO$_2$ and NaCl. We also show that similar cylindrical core-shell nanostructures derived from flat multilayers also exhibit very good absorptive and reflective properties despite the different geometry

Synesthesia and Migraine: Case Report

<p>Abstract</p> <p>Background</p> <p>Synesthesia is, as visual migraine aura, a common and fascinating perceptual phenomenon. Here we present a unique case with synesthesias exclusively during visual migraine auras.</p> <p>Case presentation</p> <p>A 40-year-old woman with a cyclic mood disorder had suffered from migraine with visual aura for several years. On several occasions she had experienced "mixing of senses" during the aura phase. Staring at strong bright light she could experience intense taste of lemon with flow from the salivary glands.</p> <p>Conclusion</p> <p>Acquired synesthesia, exclusively coincident with migraine aura, gives support to the idea of an anomalous cortical processing underlying the phenomenon.</p

Determination of Pericardial Adipose Tissue Increases the Prognostic Accuracy of Coronary Artery Calcification for Future Cardiovascular Events

Objectives: Pericardial adipose tissue (PAT) is associated with coronary artery plaque accumulation and the incidence of coronary heart disease. We evaluated the possible incremental prognostic value of PAT for future cardiovascular events. Methods: 145 patients (94 males, age 60 10 years) with stable coronary artery disease underwent coronary artery calcification (CAC) scanning in a multislice CT scanner, and the volume of pericardial fat was measured. Mean observation time was 5.4 years. Results: 34 patients experienced a severe cardiac event. They had a significantly higher CAC score (1,708 +/- 2,269 vs. 538 +/- 1,150, p 400, 3.5 (1.9-5.4; p = 0.007) for scores > 800 and 5.9 (3.7-7.8; p = 0.005) for scores > 1,600. When additionally a PAT volume > 200 cm(3) was determined, there was a significant increase in the event rate and relative risk. We calculated a relative risk of 2.9 (1.9-4.2; p = 0.01) for scores > 400, 4.0 (2.1-5.0; p = 0.006) for scores > 800 and 7.1 (4.1-10.2; p = 0.005) for scores > 1,600. Conclusions:The additional determination of PAT increases the predictive power of CAC for future cardiovascular events. PAT might therefore be used as a further parameter for risk stratification. Copyright (C) 2012 S. Karger AG, Base

Effect of "no added salt diet" on blood pressure control and 24 hour urinary sodium excretion in mild to moderate hypertension

<p>Abstract</p> <p>Background</p> <p>The incidence of Hypertension as a major cardiovascular threat is increasing. The best known diet for hypertensives is 'no added salt diet'.</p> <p>In this study we evaluated the effect of 'no added salt diet' on a hypertensive population with high dietary sodium intake by measuring 24 hour urinary sodium excretion.</p> <p>Methods</p> <p>In this single center randomized study 80 patients (60 cases and 20 controls) not on any drug therapy for hypertension with mild to moderate hypertension were enrolled. 24 hour holter monitoring of BP and 24 hour urinary sodium excretion were measured before and after 6 weeks of 'no added salt diet'.</p> <p>Results</p> <p>There was no statistically significant difference between age, weight, sex, Hyperlipidemia, family history of hypertension, mean systolic and diastolic BP during the day and at night and mean urinary sodium excretion in 24 hour urine of case and control groups. Seventy eight percent of all patients had moderate to high salt intake.</p> <p>After 6 week of 'no added salt diet' systolic and diastolic BP significantly decreased during the day (mean decrease: 12.1/6.8 mmhg) and at night (mean decrease: 11.1/5.9 mmhg) which is statistically significant in comparison to control group (P 0.001 and 0.01).</p> <p>Urinary sodium excretion of 24 hour urine decreased by 37.1 meq/d ± 39,67 mg/dl in case group which is statistically significant in comparison to control group (p: 0.001).</p> <p>Only 36% of the patients, after no added salt diet, reached the pretreatment goal of 24 hour urinary sodium excretion of below 100 meq/dl (P:0.001).</p> <p>Conclusion</p> <p>Despite modest effect on dietary sodium restriction, no added salt diet significantly decreased systolic and diastolic BP and so it should be advised to every hypertensive patient.</p> <p>Trial Registration</p> <p>Clinicaltrial.govnumber NCT00491881</p

Evaluation of early and late presentation of patients with ocular mucous membrane pemphigoid to two major tertiary referral hospitals in the United Kingdom

PURPOSE: Ocular mucous membrane pemphigoid (OcMMP) is a sight-threatening autoimmune disease in which referral to specialists units for further management is a common practise. This study aims to describe referral patterns, disease phenotype and management strategies in patients who present with either early or established disease to two large tertiary care hospitals in the United Kingdom.\ud \ud PATIENTS AND METHODS: In all, 54 consecutive patients with a documented history of OcMMP were followed for 24 months. Two groups were defined: (i) early-onset disease (EOD:<3 years, n=26, 51 eyes) and (ii) established disease (EstD:>5 years, n=24, 48 eyes). Data were captured at first clinic visit, and at 12 and 24 months follow-up. Information regarding duration, activity and stage of disease, visual acuity (VA), therapeutic strategies and clinical outcome were analysed.\ud \ud RESULTS: Patients with EOD were younger and had more severe conjunctival inflammation (76% of inflamed eyes) than the EstD group, who had poorer VA (26.7%=VA<3/60, P<0.01) and more advanced disease. Although 40% of patients were on existing immunosuppression, 48% required initiation or switch to more potent immunotherapy. In all, 28% (14) were referred back to the originating hospitals for continued care. Although inflammation had resolved in 78% (60/77) at 12 months, persistence of inflammation and progression did not differ between the two phenotypes. Importantly, 42% demonstrated disease progression in the absence of clinically detectable inflammation.\ud \ud CONCLUSIONS: These data highlight that irrespective of OcMMP phenotype, initiation or escalation of potent immunosuppression is required at tertiary hospitals. Moreover, the conjunctival scarring progresses even when the eye remains clinically quiescent. Early referral to tertiary centres is recommended to optimise immunosuppression and limit long-term ocular damage.\ud \u

Sodium intake in men and potassium intake in women determine the prevalence of metabolic syndrome in Japanese hypertensive patients: OMEGA Study

Dietary intake affects hypertension and metabolic syndrome (MS) and their management. In Japanese hypertensive patients, little evidence exists regarding the relation between diet and MS. A self-administered lifestyle questionnaire was completed by each patient at the baseline. Three dietary scores were calculated for each patient: sodium intake, potassium intake and soybean/fish intake. The relationships between dietary scores and systolic blood pressure (SBP) and diastolic blood pressure (DBP) were analyzed by multiple regression analysis. The relation between dietary intake of sodium, potassium and soybean/fish, and the presence of MS was evaluated by the Mantel–Haenszel test. A total of 9585 hypertensive patients (mean age, 64.9 years; women, 51.4%) were included in this sub-analysis. High sodium intake was significantly related to increased SBP (P=0.0003) and DBP (P=0.0130). Low potassium intake was significantly related to increased SBP (P=0.0057) and DBP (P=0.0005). Low soybean/fish intake was significantly related to increased SBP (P=0.0133). A significantly higher prevalence of MS was found in men in the highest quartile of sodium intake compared with the lower quartiles (P=0.0026) and in women in the lowest quartile of potassium intake compared with the higher quartiles (P=0.0038). A clear relation between dietary habits and blood pressure was found in Japanese hypertensive patients using a patient-administered questionnaire. Sodium and potassium intake affect MS prevalence. Dietary changes are warranted within hypertension treatment strategies

Statin use, hyperlipidaemia, and the risk of breast cancer

Hydroxymethyl glutaryl coenzyme A inhibitors (‘statins’) are carcinogenic in rodents and an increased incidence of breast cancer was reported among pravastatin users in one randomised trial. We conducted a case–control study in the General Practice Research Database to evaluate the risk of breast cancer among 50- to 79-year old women treated with statins for hyperlipidaemia. Case and control women were matched by age, general practice, duration of prescription history in the General Practice Research Database, and index date. Adjusting for history of benign breast disease, body mass index, and use of hormone replacement therapy, women currently treated with statins had an estimated relative risk for breast cancer of 1.0 (95% confidence interval 0.6–1.6) compared to women without hyperlipidaemia. Untreated hyperlipidaemia was associated with an increased risk of breast cancer (estimated relative risk 1.6; 95% confidence interval 1.1–2.5). The estimated relative risk among women currently receiving only non-statin lipid-lowering drugs was similar to that of women with untreated hyperlipidaemia (1.8; 95% confidence interval 0.9–3.4). We found no evidence for an increasing trend in breast cancer risk with increasing duration of statin use (median duration 1.8 years, maximum 8.6 years)