Statins Do Not Reduce Atrial Fibrillation After Cardiac Valvular Surgery: A Single Centre Observational Study

Introduction

Statins may theoretically reduce postoperative atrial fibrillation (AF) in patients after cardiac valvular surgery due to preservation of endothelial function and anti-ischaemic, anti-inflammatory and anti-remodelling effects.

Methods

Two hundred seventy-two patients who underwent cardiac workup and subsequently cardiac valvular surgery without AF and concomitant coronary artery bypass grafting (CABG) at our hospital were selected. Preoperative drug use and postoperative AF were recorded. AF was defined as any episode of AF longer than 10 s. In addition, results from echocardiography and blood samples were retrieved.

Results

Baseline characteristics were as follows: mean age was 65 ± 11 years, 142 (52%) patients were male, 189 (70%) had undergone aortic valve surgery and the mean left ventricular ejection fraction was 57 ± 12%. Statins were used by 79 patients (29%). Statin users, more often, had a prior percutaneous coronary intervention (25% vs 9%, p < 0.001) or CABG (24% vs 4%, p < 0.001), diabetes mellitus (22% vs 5%, p < 0.001) and more often used β-blockers (51% vs 24%, p < 0.001). Patients in the non-statin group more often had surgery on more than one valve (10% vs 3%, p = 0.043) and had a higher cholesterol level (222 ± 48 vs 190 ± 43 mg/dl, p < 0.001). Postoperative AF occurred in 54% (43/79) of the patients with and in 55% (106/193) of the patients without statins (p = 0.941). There was also no difference in the timing of onset of AF or duration of hospital stay.

Conclusion

In this observational study, statin use was not associated with a reduced incidence of AF in patients after cardiac valvular surgery.     

ACE Inhibitors Potently Reduce Vascular Inflammation,Results of an Open Proof-Of-Concept Study in the Abdominal Aortic Aneurysm

Background

Independent of their blood pressure lowering effect, ACE inhibitors are thought to reduce vascular inflammation. The clinical relevance of this effect is unclear with the current knowledge. Abdominal aortic aneurysms (AAA) are characterized by a broad, non-specific inflammatory response, and thus provide a clinical platform to evaluate the anti-inflammatory potential of ACE inhibitors.

Methods and Results

Eleven patients scheduled for open AAA repair received ramipril (5 mg/day) during 2–4 weeks preceding surgery. Aortic wall samples were collected during surgery, and compared to matched samples obtained from a biobank. An anti-inflammatory potential was evaluated in a comprehensive analysis that included immunohistochemistry, mRNA and protein analysis. A putative effect of ACE inhibitors on AAA growth was tested separately by comparing 18-month growth rate of patients on ACE inhibitors (n = 82) and those not taking ACE inhibitors (n = 204). Ramipril reduces mRNA expression of multiple pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, TNF -α, Interferon-, and MCP-1, as well as aortic wall IL-8 and MCP-1 (P = 0.017 and 0.008, respectively) protein content. The is followed by clear effects on cell activation that included a shift towards anti-inflammatory macrophage (M2) subtype. Evaluation of data from the PHAST cohort did not indicate an effect of ACE inhibitors on 18-month aneurysm progression (mean difference at 18 months: −0.24 mm (95% CI: −0.90–0.45, P = NS).

Conclusions

ACE inhibition quenches multiple aspects of vascular inflammation in AAA. However, this does not translate into reduced aneurysm growth.

Trial Registration

Nederlands Trial Register 1345.     

Previous Exposure to Statin May Reduce the Risk of Subsequent Non-Hodgkin Lymphoma: A Nationwide Population-Based Case-Control Study

Background

The purpose of this study was to investigate the association between previous exposure to statins and the risk of non-Hodgkin lymphoma (NHL).

Methods

This nationwide population-based case–control study was conducted using the National Health Insurance Research Database of Taiwan. The NHL group consisted of the patients with a first-time diagnosis of NHL between 2005 and 2008. The cases of the control group were pair-matched to the NHL group according to sex, year of birth and date of NHL diagnosis (index date). The statin administration data from both groups were retrospectively collected from the index date to January 1, 1996. The cumulative defined daily dose (cDDD) was estimated to evaluate the statin exposure. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariate logistic regression.

Results

The study population was composed of 1715 NHL patients and 16942 control subjects. The analysis revealed that previous statin administration was associated with a reduced risk of subsequent NHL with an adjusted OR of 0.52 (95% CI, 0.43–0.62). Additionally, there was a dose-response relationship between statin administration and the risk of NHL. The adjusted ORs were 0.63 (95% CI, 0.46–0.86), 0.58 (95% CI, 0.42–0.79), 0.51 (95% CI, 0.38–0.67), and 0.36 (95% CI, 0.24–0.53) for the subjects with statin administrations of fewer than 28, 28 to 90, 91 to 365, and more than 365 cDDDs, respectively, relative to the subjects without any statin administration.

Conclusions

The results of this study suggest that previous statin administration is associated with a lower risk of subsequent NHL. As statins are widely used medications, the magnitude of the risk reduction may have a substantial influence on public health. Further studies to confirm our findings are warranted.     

Statin Intolerance: A Review and Update

ObjectiveTo review the evidence of existing literature on the management of statin intolerance.MethodsWe searched for literature pertaining to statin intolerance and treatments in PubMed. We reviewed articles published between 2005 and 2022.ResultsStatin-associated myalgia is the most common adverse effect of statin therapy and the most common reason for statin discontinuation. The risk factors for statin intolerance include unexplained muscle pain with other lipid-lowering therapy, unexplained cramps, a history of increased creatine kinase levels, a family history of muscle symptoms, and a family history of muscle symptoms with lipid therapy. Vitamin D repletion and coenzyme Q supplementation may help alleviate the musculoskeletal effects of statins. Trials of different types of statins and different dosing regimens are recommended to improve tolerability. The use of statins in individuals who perform regular exercise requires closer attention to muscular symptoms and creatine kinase levels; however, it does not preclude the use of statins.ConclusionManagement of the adverse effects of statin therapy and improving statin tolerability are key to achieving optimum cardiovascular benefits. Identifying statin-associated adverse effects and managing them appropriately can reduce unnecessary statin discontinuation and subsequently provide longer cardiovascular protection.     

Statins Attenuate Helicobacter pylori CagA Translocation and Reduce Incidence of Gastric Cancer: In Vitro and Population-Based Case-Control Studies

Gastric cancer is the second leading cause of cancer-related death worldwide. The correlation of Helicobacter pylori and the etiology of gastric cancer was substantially certain. Cholesterol-rich microdomains (also called lipid rafts), which provide platforms for signaling, are associated with H. pylori-induced pathogenesis leading to gastric cancer. Patients who have been prescribed statins, inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, have exhibited a reduced risk of several types of cancer. However, no studies have addressed the effect of statins on H. pylori-associated gastric cancer from the antineoplastic perspective. In this study, we showed that treatment of gastric epithelial cells with simvastatin reduced the level of cellular cholesterol and led to attenuation of translocation and phosphorylation of H. pylori cytotoxin-associated gene A (CagA), which is recognized as a major determinant of gastric cancer development. Additionally, a nationwide case-control study based on data from the Taiwanese National Health Insurance Research Database (NHIRD) was conducted. A population-based case-control study revealed that patients who used simvastatin exhibited a significantly reduced risk of gastric cancer (adjusted odds ratio (OR) = 0.76, 95% confidence interval (CI) = 0.70–0.83). In patients exhibiting H. pylori infection who were prescribed simvastatin, the adjusted OR for gastric cancer was 0.25 (95% CI = 0.12–0.50). Our results combined an in vitro study with a nationwide population analysis reveal that statin use might be a feasible approach to prevent H. pylori-associated gastric cancer.     

Pigment Epithelium-Derived Factor (PEDF) Peptide Eye Drops Reduce Inflammation,Cell Death and Vascular Leakage in Diabetic Retinopathy in Ins2Akita Mice

Inflammation, neurodegeneration and microvascular irregularities are included in the spectrum of defects associated with diabetic retinopathy. Here, we evaluated intraocular deliverability features of two pigment epithelium-derived factor (PEDF) derivatives given as eye drops and their efficacy in modulating diabetes-induced retinal complications. The antiangiogenic PEDF60–77 (P60) and neuroprotective PEDF78–121 (P78) derivatives were applied to Ins2^Akita mouse eyes once a week for 15 wks at the onset of hyperglycemia. Peptides, labeled with Alexa Fluor 488, were observed penetrating the cornea by 1–4 h and gained access to the ciliary body, retinal pigment epithelium (RPE)-choroid complex, retina microvasculature and vitreous. Peak vitreous levels were 0.2 μg/mL for P60 and 0.9 μg/mL for P78 after 0.5 and 4 h, respectively. Both peptides reduced vascular leakage by ~60% and increased zona occludens 1 (ZO1) and occludin expression in the microvasculature to nondiabetic levels. P60 induced pERK1/2 and P78 promoted pAKT in Muller glia, two signals that were dampened in diabetic conditions. Pharmacologically inhibiting AKT signaling in the retina blocked effects of the peptides on ZO1 and occludin expression. P78 reduced levels of 9/20 cytokines in diabetic vitreous including interferon (IFN)-γ, interleukin (IL)-6, IL-3 and tumor necrosis factor (TNF)-α. P60 lowered levels of 6/20 cytokines but was less effective than P78. Neuroprotective P78 prevented diabetes-induced microglia activation by ~60%, retinal ganglion cell (RGC) death by ~22% and inner plexiform layer thinning by ~13%. In summary, we provide evidence that PEDF bioactive derivatives gained access to the retina by topical delivery and validated their efficacy in reducing diabetic retinopathy complications. Our findings argue for glia regulation of microvascular leakage and an early root cause for RGC degeneration embedded in microglia activation.     

Betamethasone: A Dermatological Clinical Evaluation

The purpose of this study was to determine under carefully controlled clinical conditions the relative anti-inflammatory and anti-pruritic action of betamethasone as compared with prednisone and a placebo. A total of 130 consecutive patients with atopic dermatitis, primary irritant dermatitis, nummular eczema, allergic eczematous contact dermatitis, sweat retention, seborrheic dermatitis and pruritus were selected for study. Under the conditions of this clinical trial, the samples indicated a difference in anti-inflammatory and anti-pruritic response to the therapeutic agents used. The difference between betamethasone and the placebo was highly significant, and the difference in these measured responses was studied on the basis of a careful evaluation and statistically. The result of this study corroborates statistically our clinical impression regarding the therapeutic effect of betamethasone.     

GPA: A Statistical Approach to Prioritizing GWAS Results by Integrating Pleiotropy and Annotation

Results from Genome-Wide Association Studies (GWAS) have shown that complex diseases are often affected by many genetic variants with small or moderate effects. Identifications of these risk variants remain a very challenging problem. There is a need to develop more powerful statistical methods to leverage available information to improve upon traditional approaches that focus on a single GWAS dataset without incorporating additional data. In this paper, we propose a novel statistical approach, GPA (Genetic analysis incorporating Pleiotropy and Annotation), to increase statistical power to identify risk variants through joint analysis of multiple GWAS data sets and annotation information because: (1) accumulating evidence suggests that different complex diseases share common risk bases, i.e., pleiotropy; and (2) functionally annotated variants have been consistently demonstrated to be enriched among GWAS hits. GPA can integrate multiple GWAS datasets and functional annotations to seek association signals, and it can also perform hypothesis testing to test the presence of pleiotropy and enrichment of functional annotation. Statistical inference of the model parameters and SNP ranking is achieved through an EM algorithm that can handle genome-wide markers efficiently. When we applied GPA to jointly analyze five psychiatric disorders with annotation information, not only did GPA identify many weak signals missed by the traditional single phenotype analysis, but it also revealed relationships in the genetic architecture of these disorders. Using our hypothesis testing framework, statistically significant pleiotropic effects were detected among these psychiatric disorders, and the markers annotated in the central nervous system genes and eQTLs from the Genotype-Tissue Expression (GTEx) database were significantly enriched. We also applied GPA to a bladder cancer GWAS data set with the ENCODE DNase-seq data from 125 cell lines. GPA was able to detect cell lines that are biologically more relevant to bladder cancer. The R implementation of GPA is currently available at http://dongjunchung.github.io/GPA/.     

Statins and the Risk of Lung Cancer: A Meta-Analysis

Purpose

Several epidemiologic studies have evaluated the association between statins and lung cancer risk, whereas randomized controlled trials (RCTs) on cardiovascular outcomes provide relevant data as a secondary end point. We conducted a meta-analysis of all relevant studies to examine this association.

Methods

A systematic literature search up to March 2012 was performed in PubMed database. Study-specific risk estimates were pooled using a random-effects model.

Results

Nineteen studies (5 RCTs and 14 observational studies) involving 38,013 lung cancer cases contributed to the analysis. They were grouped on the basis of study design, and separate meta-analyses were conducted. There was no evidence of an association between statin use and risk of lung cancer either among RCTs (relative risk [RR] 0.91, 95% confidence interval [CI] 0.76–1.09), among cohort studies (RR 0.94, 95% CI 0.82–1.07), or among case-control studies (RR 0.82, 95% CI 0.57–1.16). Low evidence of publication bias was found. However, statistically significant heterogeneity was found among cohort studies and among case-control studies. After excluding the studies contributing most to the heterogeneity, summary estimates were essentially unchanged.

Conclusion

The results of our meta-analysis suggest that there is no association between statin use and the risk of lung cancer.     

Anti-TNF Therapy Reduces Serum Levels of Chemerin in Rheumatoid Arthritis: A New Mechanism by Which Anti-TNF Might Reduce Inflammation

Background

Chemerin is a specific chemoattractant for macrophages and dendritic cells (DC). In addition, it can rapidly stimulate macrophage adhesion to extracellular matrix proteins and adhesion molecules and is able to activate fibroblast-like synoviocytes (FLS), suggesting a role in the pathogenesis of rheumatoid arthritis (RA). Chemerin is also an adipocytokine that has been related to the inflammatory state of endothelial cells and as such could be involved in the changes in endothelial cells in RA and perhaps increased cardiovascular morbidity. We investigated whether anti-Tumor Necrosis Factor (TNF) treatment affects chemerin levels.

Materials and Methods

49 patients with active RA (disease activity score evaluated in 28 joints (DAS28) ≥3.2) were started on adalimumab therapy. Blood was drawn from patients while fasting at baseline and 16 weeks after initiation of treatment. Chemerin serum levels were measured by ELISA and related to disease activity, mediators of inflammation and known risk factors for cardiovascular disease.

Results

Adalimumab therapy reduced chemerin serum levels, which was correlated with the reduction in DAS28 (r = 0.37, p = 0.009). In addition, the decrease in chemerin serum levels after anti-TNF treatment was associated with the decrease in serum levels of IL-6 (r = 0.39, p = 0.033) and macrophage migration inhibitory factor (MIF) (r = 0.31, p = 0.049). Baseline chemerin serum levels were not related to traditional risk factors for atherosclerosis, except perhaps for smoking (p = 0.07).

Conclusions

This exploratory study shows that adalimumab therapy lowers chemerin levels, which is associated with the reduction in disease activity parameters, and inflammatory mediators IL-6 and MIF. This suggests a possible involvement of chemerin in the migration/retention of macrophages in the synovium.

Trial Registration Nederlands Trial Register

NTR 857     

Vascular Cognitive Disorder. A Biological and Clinical Overview

Although vascular dementia (VaD) represents the second most common cause of dementia after Alzheimer’s disease (AD) in the elderly, and is referred as the “silent epidemic of the twenty-first century”, there is still a controversy on terminology, classification and diagnostic criteria of VaD. The diagnosis of VaD resides in clinical criteria determining a cognitive impairment, the presence of cerebrovascular disease and, only in the case of post-stroke dementia or multi-infarct dementia, a temporal relationship between these. The search for a reliable biochemical tests helping in the diagnosis of VaD is so far not available. Several vascular risk factors have a role in the development of VaD and their identification and treatment are among the major aspects of management of VaD. A new line of research in this field is the study of genetic factors underlying vascular cognitive impairment which are: (1) genes predisposing to cerebrovascular disease, and (2) genes that influence brain tissue responses to cerebrovascular lesions. Evidence in favour of a coexistence of vascular and degenerative components in the pathogenesis of dementia in an elderly population comes from neuropathological and epidemiological studies. There is now a great debate whether VaD and AD are more than common coexisting unrelated pathologies and, instead, represent different results of synergistic pathological mechanisms. Preventive approaches aiming at reducing incident VaD by targeting patients at risk of cerebrovascular disease (primary prevention), or acting on patients after a stroke (secondary prevention) to prevent stroke recurrence and the progression of brain changes associated with cognitive impairment are mandatory therapeutic strategies.     

Statin use and peripheral sensory perception: A pilot study

Objectives. Peripheral sensory neuropathy is a neurological deficit resulting in decreased detection of sensation through the peripheral nervous system. Peripheral sensory neuropathy is commonly diagnosed with the use of a monofilament and either a tuning fork or neurothesiometer. Statins are a widely used medication and there has been some debate of association with their use and peripheral sensory neuropathy. This pilot study aimed to test the sensory perception of participants with long-term statin use and compare these results to their peers who were not taking statins.

Methods. Thirty participants were recruited and equally divided into a statin and non-statin group. Healthy participants were screened by their medical and medication history, Australian Type 2 Diabetes Risk assessment, and random blood glucose level. An assessor who was blinded to the participant group conducted sensory assessments using a 10?g monofilament and neurothesiometer.

Results. There was no difference in monofilament testing results between the groups. The statin group was less sensate at the styloid process (p?=?0.031) and medial malleolus (p?=?0.003) than the control group. Results at the hallux were not statistically significant (p?=?0.183).

Conclusion. This result is suggestive of a potential association between long-term statin use and a decrease in peripheral sensory perception. This may be because of peripheral sensory neuropathy. Limitations such as consideration of participant height, participant numbers, and inability to analyze results against statin groups are reported. As statins are a life-saving medication, careful consideration should be applied to these results and further research be conducted to determine if these results are applicable to larger populations.     

Angiogenesis and Inflammation Signaling Are Targets of Beer Polyphenols on Vascular Cells

Emerging evidence indicates that chronic inflammation and oxidative stress cluster together with angiogenic imbalance in a wide range of pathologies. In general, natural polyphenols present health‐protective properties, which are likely attributed to their effect on oxidative stress and inflammation. Hops used in beer production are a source of polyphenols such as xanthohumol (XN), and its metabolites isoxanthohumol (IXN) and phytoestrogen 8‐prenylnaringenin (8PN). Our study aimed to evaluate XN, IXN, and 8PN effects on angiogenesis and inflammation processes. Opposite in vitro effects were observed between 8PN, stimulating endothelial and smooth muscle cell (SMC) growth, motility, invasion and capillary‐like structures formation, and XN and IXN, which inhibited them. Mouse matrigel plug and rat skin wound‐healing assays confirmed that XN and IXN treatments reduced vessel number as well as serum macrophage enzymatic activity, whereas 8PN increased blood vessels formation in both assays and enzyme activity in the wound‐healing assay. A similar profile was found for serum inflammatory interleukin‐1β quantification, in the wound‐healing assay. Our data indicate that whereas 8PN stimulates angiogenesis, XN and IXN manifested anti‐angiogenic and anti‐inflammatory effects in identical conditions. These findings suggest that the effects observed for individual compounds on vascular wall cells must be carefully taken into account, as these polyphenols are metabolized after in vivo administration. The modulation of SMC proliferation and migration is also of special relevance, given the role of these cells in many pathological conditions. Furthermore, these results may provide clues for developing useful therapeutic agents against inflammation‐ and angiogenesis‐associated pathologies. J. Cell. Biochem. 111: 1270–1279, 2010. © 2010 Wiley‐Liss, Inc.     

A Key Role for the Endothelium in NOD1 Mediated Vascular Inflammation: Comparison to TLR4 Responses

Understanding the mechanisms by which pathogens induce vascular inflammation and dysfunction may reveal novel therapeutic targets in sepsis and related conditions. The intracellular receptor NOD1 recognises peptidoglycan which features in the cell wall of Gram negative and some Gram positive bacteria. NOD1 engagement generates an inflammatory response via activation of NFκB and MAPK pathways. We have previously shown that stimulation of NOD1 directly activates blood vessels and causes experimental shock in vivo. In this study we have used an ex vivo vessel-organ culture model to characterise the relative contribution of the endothelium in the response of blood vessels to NOD1 agonists. In addition we present the novel finding that NOD1 directly activates human blood vessels. Using human cultured cells we confirm that endothelial cells respond more avidly to NOD1 agonists than vascular smooth muscle cells. Accordingly we have sought to pharmacologically differentiate NOD1 and TLR4 mediated signalling pathways in human endothelial cells, focussing on TAK1, NFκB and p38 MAPK. In addition we profile novel inhibitors of RIP2 and NOD1 itself, which specifically inhibit NOD1 ligand induced inflammatory signalling in the vasculature. This paper is the first to demonstrate activation of whole human artery by NOD1 stimulation and the relative importance of the endothelium in the sensing of NOD1 ligands by vessels. This data supports the potential utility of NOD1 and RIP2 as therapeutic targets in human disease where vascular inflammation is a clinical feature, such as in sepsis and septic shock.     

Synergistic Binding of Vascular Endothelial Growth Factor-A and Its Receptors to Heparin Selectively Modulates Complex Affinity

Angiogenesis is a highly regulated process orchestrated by the VEGF system. Heparin/heparan sulfate proteoglycans and neuropilin-1 (NRP-1) have been identified as co-receptors, yet the mechanisms of action have not been fully defined. In the present study, we characterized molecular interactions between receptors and co-receptors, using surface plasmon resonance and in vitro binding assays. Additionally, we demonstrate that these binding events are relevant to VEGF activity within endothelial cells. We defined interactions and structural requirements for heparin/HS interactions with VEGF receptor (VEGFR)-1, NRP-1, and VEGF₁₆₅ in complex with VEGFR-2 and NRP-1. We demonstrate that these structural requirements are distinct for each interaction. We further show that VEGF₁₆₅, VEGFR-2, and monomeric NRP-1 bind weakly to heparin alone yet show synergistic binding to heparin when presented together in various combinations. This synergistic binding appears to translate to alterations in VEGF signaling in endothelial cells. We found that soluble NRP-1 increases VEGF binding and activation of VEGFR-2 and ERK1/2 in endothelial cells and that these effects require sulfated HS. These data suggest that the presence of HS/heparin and NRP-1 may dictate the specific receptor type activated by VEGF and ultimately determine the biological output of the system. The ability of co-receptors to fine-tune VEGF responsiveness suggests the possibility that VEGF-mediated angiogenesis can be selectively stimulated or inhibited by targeting HS/heparin and NRP-1.     

功能蛋白的O-糖基化和p38磷酸化共同参与调控单核细胞对血管内皮的粘附和侵袭

探讨单核细胞在炎症因子刺激下通过功能蛋白O-糖基化和p38 MAPK磷酸化、调控其对血管内皮的粘附和侵袭的分子机制。将IFN-γ与LPS体外共刺激后的THP-1细胞加至单层血管内皮细胞EA.hy926共培养,观察单核细胞对血管内皮的粘附和侵袭;并通过测量电阻变化来反应血管内皮通透性的改变。采用Western blot方法检测单核细胞THP-1中p38 MAPK磷酸化的变化,O-GLcNAc糖基转移酶（OGT）和O-GLcNAc糖基化蛋白表达量的变化。分析验证p38 MAPK抑制剂对IFN-γ与LPS诱导的单核细胞对血管内皮粘附和迁移的影响,同时检测OGT、O-GLcNAc糖基化蛋白差异表达的影响。结果显示,IFN-γ与LPS可以共作用促进THP-1对血管内皮的粘附和侵袭,降低血管内皮通透性。同时激活p38 MAPK,此过程与OGT及O-GLcNAc糖基化蛋白表达降低相关。采用p38抑制剂预处理,可逆转上述IFN-γ与LPS诱导的生物学变化。综上,在炎症反应中,单核细胞对血管内皮的粘附和侵袭力的变化受功能蛋白糖基化和磷酸化的双向调控。     

Retinal Vascular Caliber Is Associated with Cardiovascular Biomarkers of Oxidative Stress and Inflammation: The POLA Study

Purpose

Retinal vascular caliber has been linked with increased cardiovascular risk and is predictive of cardiovascular pathology, including stroke and coronary heart disease. Oxidative stress, as well as inflammatory mechanisms, plays a major role in the pathogenesis and progression of atherosclerosis, plaque rupture and vascular thrombotic propensity. The purpose of this study is to explore the relationship between retinal vascular calibers and biomarkers of oxidative stress and inflammation, in subjects free of cardiovascular pathology.

Patients and Methods

Cross-sectional analysis from a community-dwelling cohort comprising 1224 individuals aged 60 years and over, without a history of coronary or peripheral artery disease or stroke. Retinal vascular caliber was measured from fundus photographs using semi-automated standardized imaging software. Oxidative stress was evaluated using plasma superoxide dismutase 2 and glutathione peroxidase (GPx-3) activities, and inflammatory state was assessed using plasma high sensitivity C-reactive protein (hsCRP) and orosomucoid.

Results

In a multivariate model controlling for cardiovascular risk factors, larger retinal arteriolar caliber was independently related to higher level of GPx-3 activity (p = 0.003) whereas larger venular caliber was associated with higher levels of hsCRP (p = 0.0001) and orosomucoid (p = 0.01).

Conclusion

In the present study, biomarkers of oxidative stress regulation and inflammation were independently associated with retinal vascular calibers. This suggests that an assessment of retinal vessels may offer early and non-invasive detection of subclinical vascular pathology.     

CAPE: An R Package for Combined Analysis of Pleiotropy and Epistasis

Contemporary genetic studies are revealing the genetic complexity of many traits in humans and model organisms. Two hallmarks of this complexity are epistasis, meaning gene-gene interaction, and pleiotropy, in which one gene affects multiple phenotypes. Understanding the genetic architecture of complex traits requires addressing these phenomena, but interpreting the biological significance of epistasis and pleiotropy is often difficult. While epistasis reveals dependencies between genetic variants, it is often unclear how the activity of one variant is specifically modifying the other. Epistasis found in one phenotypic context may disappear in another context, rendering the genetic interaction ambiguous. Pleiotropy can suggest either redundant phenotype measures or gene variants that affect multiple biological processes. Here we present an R package, R/cape, which addresses these interpretation ambiguities by implementing a novel method to generate predictive and interpretable genetic networks that influence quantitative phenotypes. R/cape integrates information from multiple related phenotypes to constrain models of epistasis, thereby enhancing the detection of interactions that simultaneously describe all phenotypes. The networks inferred by R/cape are readily interpretable in terms of directed influences that indicate suppressive and enhancing effects of individual genetic variants on other variants, which in turn account for the variance in quantitative traits. We demonstrate the utility of R/cape by analyzing a mouse backcross, thereby discovering novel epistatic interactions influencing phenotypes related to obesity and diabetes. R/cape is an easy-to-use, platform-independent R package and can be applied to data from both genetic screens and a variety of segregating populations including backcrosses, intercrosses, and natural populations. The package is freely available under the GPL-3 license at http://cran.r-project.org/web/packages/cape.

This is a PLOS Computational Biology Software Article

     

Statins: mechanism of action and effects

The beneficial effects of statins are the result of their capacity to reduce cholesterol biosyntesis, mainly in the liver, where they are selectively distributed, as well as to the modulation of lipid metabolism, derived from their effect of inhibition upon HMG-CoA reductase. Statins have antiatherosclerotic effects, that positively correlate with the percent decrease in LDL cholesterol. In addition, they can exert antiatherosclerotic effects independently of their hypolipidemic action. Because the mevalonate metabolism generates a series of isoprenoids vital for different cellular functions, from cholesterol synthesis to the control of cell growth and differentiation, HMG-CoA reductase inhibition has beneficial pleiotropic effects. Consequently, statins reduce significantly the incidence of coronary events, both in primary and secondary prevention, being the most efficient hypolipidemic compounds that have reduced the rate of mortality in coronary patients. Independent of their hypolipidemic properties, statins interfere with events involved in bone formation and impede tumor cell growth.     

Statin Use and Risk of Prostate Cancer: A Meta-Analysis of Observational Studies

Background

Emerging evidence suggests that statins may decrease the risk of cancers. However, available evidence on prostate cancer (PCa) is conflicting. We therefore examined the association between statin use and risk of PCa by conducting a detailed meta-analysis of all observational studies published regarding this subject.

Methods

Literature search in PubMed database was undertaken through February 2012 looking for observational studies evaluating the association between statin use and risk of PCa. Before meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using random-effects model (DerSimonian and Laird method). Subgroup analyses, sensitivity analysis and cumulative meta-analysis were also performed.

Results

A total of 27 (15 cohort and 12 case-control) studies contributed to the analysis. There was heterogeneity among the studies but no publication bias. Statin use significantly reduced the risk of both total PCa by 7% (RR 0.93, 95% CI 0.87–0.99, p = 0.03) and clinically important advanced PCa by 20% (RR 0.80, 95% CI 0.70–0.90, p<0.001). Long-term statin use did not significantly affect the risk of total PCa (RR 0.94, 95% CI 0.84–1.05, p = 0.31). Stratification by study design did not substantially influence the RR. Furthermore, sensitivity analysis confirmed the stability of results. Cumulative meta-analysis showed a change in trend of reporting risk from positive to negative in statin users between 1993 and 2011.

Conclusions

Our meta-analysis provides evidence supporting the hypothesis that statins reduce the risk of both total PCa and clinically important advanced PCa. Further research is needed to confirm these findings and to identify the underlying biological mechanisms.