The Emerging Role of Interleukin-1�� in Autoinflammatory Diseases

The autoinflammatory syndromes are a group of multisystem disorders characterized by recurrent episodes of fever and systemic inflammation affecting the eyes, joints, skin, and serosal surfaces in the absence of an immune reaction. Recent advances have revealed the importance of interleukin-1β, not only in the pathogenesis of many of these rare inherited diseases, but also in acquired diseases. The development and availability of anti-interleukin-1β therapeutics have introduced the possibility of proof-of-concept studies, which are likely to further widen this field.     

Genetics and Personalized Medicine—a Role in Statin Therapy?

A number of meta-analyses of cohort studies have assessed the impact of glycemic load (GL) and glycemic index (GI) on cardiovascular outcomes. The picture that emerges is that for women, a significant association appears to exist between the consumption of high GL/GI diets and increased cardiovascular disease (CVD) risk. This association appears to be stronger in those with greater adiposity and possibly in those with diabetes, although these findings are not uniform. There is also an indication that raised CRP levels may be reduced, which has special implications for women whose CRP levels, as an emerging CVD risk factor, may be higher than men. For men, the situation is not as clear-cut. Although some studies show association, the meta-analyses have not demonstrated a significant direct association with CVD, despite current evidence that risk factors, including LDL-C, may be reduced on low-GI diets. Moreover, in a recent meta-analysis, increases in dietary GL have been associated with increased risk of diabetes, another CVD risk factor, in both men and women. Studies in men expressing relative risk of CVD in relation to GL and GI, with corresponding confidence intervals, are needed to provide the necessary power for future meta-analyses on this topic.     

The Current and Future Role of the Novel Oral Anticoagulants—Indications Beyond Atrial Fibrillation

The direct thrombin inhibitors and Factor-Xa inhibitors are novel oral anticoagulants which are gaining rapid acceptance not only as alternatives to warfarin, but also as recommended first line agents for use as stroke prophylaxis in patients with non-valvular atrial fibrillation.There are, however, other patient settings in which anticoagulation is either indicated or has a potential role. Warfarin is still the predominant anticoagulant used for the treatment and prevention of venous thromboembolic events including deep vein thrombosis and pulmonary embolism as well as in patients with mechanical prosthetic heart valves. In this article, we review the current evidence for the use of dabigatran, rivaroxaban, apixaban and edoxaban in these settings. A summary of suggested regimens utilising these agents is provided. Importantly, in addition, attention is also drawn to clinical scenarios in which use of such agents is considered inappropriate.     

Genetics—Current and Future Role in the Prevention and Management of Coronary Artery Disease

Purpose of Review

The purpose of this study is to review genetic risk variants for coronary artery disease (CAD) and how they will change the management and prevention of CAD currently and in the future.

Recent Findings

Through the efforts of international consortia, 58 genetic risk variants for CAD of genome-wide significance have been replicated in appropriate independent populations. Only one third of these variants mediate their risk through known conventional risk factors for CAD. Thus, unknown mechanisms contribute to CAD. Secondly, the genetic risk is proportional to the total number of risk variants rather than the intensity of any risk factor. Thirdly, the availability of the genetic risk variants enables one to perform Mendelian randomization (MR) studies since they are randomized at conception, not confounded, fixed for life, and can be used to determine if a risk factor is causative or just a marker. MR can also be used to determine the safety and efficacy of a gene product targeted for drug therapy. Genetic risk variants have been shown to successfully risk stratify for CAD in both primary and secondary preventions.

Summary

Contrary to dogma, MR documents that plasma HDL-C is not protective of CAD. The use of genetic risk score (GRS) for CAD is shown to be more effective in risk stratifying for CAD than the Framingham risk score and independent of the conventional risk factors including family history. Furthermore, the GRS predicts the response to statin therapy in primary and secondary preventions. The use of GRS could represent a paradigm shift in the prevention of CAD.

     

Is There a Role for Genetics in the Prevention of Sudden Cardiac Death?

The identification of patients at risk for sudden cardiac death (SCD) is fundamental for both acquired cardiovascular diseases (such as coronary artery diseases, CAD) and inherited arrhythmia syndromes (such as the long‐QT syndrome, LQTS). Genetics may play a role in both situations, although the potential to exploit this information to reduce the burden of SCD varies among these two groups. Concerning acquired cardiovascular diseases, which affect most of the general population, preliminary data suggest an association between genetics and the risk of dying suddenly. The maximal utility, instead, is reached in inherited arrhythmia syndromes, where the discovery of monogenic diseases such as LQTS tracked the way for the first genotype‐phenotype correlations. The aim of this review is to provide a general overview focusing on the current genetic knowledge and on the present and future applicability for prevention in these two populations at risk for SCD.     

The Emerging Role of Cardiac Resynchronization Therapy in Milder Heart Failure: Are We Implanting Too Late for Response?

The role of cardiac resynchronization therapy in mild heart failure has become a focus of attention with the publication of recent clinical trials. We present a review of the data supporting implantation of cardiac resynchronization devices in early stage heart failure. In addition, we present evidence that may suggest patients are often implanted too late for clinical benefit, potentially contributing to the relatively high nonresponder rate seen in randomized trials and clinical practice.     

Which Multidrug-Resitant Bacteria are Emerging in Patients with Hematological Malignancies?: One-Year Report

The aim of this retrospective, observational study was to evaluate the outcomes of bacteremia attacks during neutropenic episodes caused by chemotherapy in patients with hematological cancers by assessing mortality, involved pathogens, antimicrobial therapy and treatment responses. Patients who were older than 14 years of age and developed at least one neutropenic episode after chemotherapy to treat hematological cancer between November 2011 and November 2012 were included in the study. We retrospectively collected demographic, treatment, and survival data for 68 patients with 129 neutropenic episodes. The mean age was 59.36 ± 15.22 years (range 17–80 years), and 41 cases were male. The mean Multinational Association of Supportive Care in Cancer score was 19.56 ± 9.04. A total of 37 (28 %) bacteremia attacks were recorded in 20 cases (29 %). Fatality rates were 50 % in the six cases with bacteremia caused by carbapenem-resistant Gram-negative bacteria; death occurred in two patients with carbapenem-resistant Acinetobacter baumannii and in one patient with carbapenem-resistant Pseudomonas aeruginosa. Clinical and microbiological responses were achieved using PIP-TAZ or CEP-SUL treatment in 80 % (16/20) of the cases with bacteremia caused by carbapenem-sensitive Gram-negative bacteria (CS-GNB). During 547 colonization-days in 21 (30 %) vancomycin-resistant enterococci (VRE)-colonized cases among 68 patients, vancomycin-resistant Enterococcus faecium bacteremia developed in two patients. Non-carbapenem-based therapy can cure most bacteremia attacks caused by CS-GNB in patients with hematological cancer. However, bacteremia and other infections caused by drug-resistant pathogens, such as A. baumannii, P. aeruginosa, and VRE, are a growing concern in hematological patients.     

The Role of the MAP-Kinase Superfamily in β-Amyloid Toxicity

The mitogen-activated protein kinase (MAP kinase) pathway participates in a number of reactions of the cell when responding to various external stimuli. These stimuli include growth factor binding to its receptor as well as stressful situations such as hypoxia and oxidative stress. It has been postulated that one of the mechanisms by which -amyloid exerts its toxic effects is to produce oxidative stress. This study therefore investigated whether the MAP-kinase pathway was activated in cells following exposure to -amyloid. Neuroblastoma (N2) cells were used in all experiments. The cells were exposed to 50, 100, and 500 M glutamate, and 10, 30, and 50 M -amyloid, for 24 h. The methyl–thiazolyl tetrazolium salt (MTT) assay was performed to determine the degree of toxicity. The generation of hydrogen peroxide was detected by fluorescence microscopy using the dye dihydrochlorofluorescein diacetate (DCDHF). Extracellular-signal-regulated kinase (ERK) and p38 MAP-kinase phosphorylation, as representatives of the MAP-kinase pathway, was determined. Treating N2 cells with -amyloid resulted in a greater than 50% reduction in cell viability. These cells also showed a significantly higher presence of hydrogen peroxide. Western Blot analysis revealed that the phosphorylation of p38 MAP kinase was dose-dependently increased in cells exposed to glutamate and -amyloid. On the other hand, the phosphorylation of ERK was significantly reduced in these cells. These data therefore suggest that the toxic effects of -amyloid involve the generation of hydrogen peroxide, leading to the activation of p38 and the down-regulation of ERK.     

The Role of Tumor Necrosis Factor-α Receptors in Atherosclerosis

Tumor necrosis factor (TNF-α)-α is a cytokine exhibiting a plethora of activities involved in inflammation, immune regulation, and energy metabolism. TNF is produced by many cell types, including cells found in atherosclerotic lesions, such as activated monocytes or macrophages, T and B lymphocytes, mast cells, and smooth muscle cells. Two receptors mediate the functions of TNF, and both receptors are also present on cells of the artery wall and on cells involved in lesion development. Mice genetically engineered to lack expression of TNF and each of its receptors are now available and are being used to dissect the role of these molecules in protection from or development of atherosclerosis. The role of TNF receptors in atherosclerosis is the primary focus of this review.     

The Role of MIP-1α in Experimental Hypersensitivity Pneumonitis

S. rectivirgula (SR) causes Farmers Lung Disease, a classic example of hypersensitivity pneumonitis (HP). We utilized a model of experimental hypersensitivity pneumonitis (EHP), antibody to MIP-1 and MIP-1^–/– mice, to test the hypothesis that MIP-1 is essential in the development of EHP. Treatment of C57BI/6 mice with anti-MIP-1 antibody did not change the extent of pulmonary histology abnormalities, BALF cell number or characteristics, or BALF concentration of IL12p40, TNF, IL1 and IL6, after an i.t. challenge with SR. MIP-1^–/– animals responded similarly to wild-type (wt) animals in the extent and nature of pulmonary histologic changes and BALF cell number and type after a single i.t. injection of SR There was a dose-response relationship between the amount of SR and BALF IL12p40, MCP-1 and IL6 in both strains, and MIP-1 in wild-type animals. We next transferred SR cultured spleen cells from SR sensitized mice (both wt and MIP-1^–/–) to naïve recipients. Lung histology and BALF characteristics after SR i.t. challenge of the recipients were used to determine if adoptive transfer had occurred. Cultured cells from MIP-1^–/– animals were fully capable of transferring EHP to recipients. There was no difference of BALF TNF, IL6 and IL1 between the strains, but there was more MCP-1 and IL12p40 in the MIP-1^–/– mice than in the control mice. MIP-1 is not necessary for the recruitment of cells into the lung and BALF after i.t. administration of SR, or the development of cells able to adoptively transfer EHP.     

The Genetics of Juvenile Idiopathic Arthritis: What Is New in 2010?

Juvenile idiopathic arthritis (JIA), the most common cause of chronic arthritis in children, is believed to be influenced by genetic factors. Recent studies on the genetics of JIA have not only validated proposed genetic associations but have also led to the recognition of novel genetic associations. Studies of specific genes have been modeled on the premise of shared autoimmunity, wherein genetic variants that predispose to other autoimmune phenotypes may also confer susceptibility to JIA. The advent of genome-wide association studies has accelerated the detection of non-HLA susceptibility loci in other autoimmune phenotypes and is likely to uncover novel JIA-associated variants as well. This review highlights recent genetic investigations of JIA.     

Acquired Immunodeficiency Syndrome—Related Malignancies in the Era of Highly Active Antiretroviral Therapy

Since the beginning of the acquired immunodeficiency syndrome (AIDS) epidemic, malignancies have been an important feature of this disease. Several cancers, including Kaposi sarcoma (KS), certain aggressive B-cell lymphomas, and cervical cancer, are considered AIDS-defining when they occur in patients infected with human immunodeficiency virus. Most AIDS-defining tumors are associated with one of 3 DNA viruses: KS-associated herpesvirus, Epstein-Barr virus, or human papillomavirus. With the introduction of highly active antiretroviral therapy (HAART), the incidence of KS and certain lymphomas has decreased, whereas that of other tumors, such as cervical cancer, has undergone little change. Several new drugs and therapies have been developed for KS and AIDS-related lymphomas, and these treatments, plus the development of HAART, have contributed to improvements in morbidity and mortality. At the same time, the improved overall survival of patients with HAART has contributed to an increase in the number of patients living with AIDS in developed countries such as the United States. With the development of HAART and improved prevention and treatment of opportunistic infections, an increasing percentage of the deaths in AIDS patients have been from malignancies. Strategies for prevention, screening, and therapy remain important areas of research in this developing field.     

The Role of Calcium in the Prevention of Cardiovascular Disease—A Review of Observational Studies and Randomized Clinical Trials

Calcium is a mineral that is important for bone health and has also been suggested to play a role in the prevention of cardiovascular disease (CVD). Lately, the potential effects of both inadequate and excessive calcium intake have received growing attention. In this review, we summarize the evidence from experimental, epidemiologic, and clinical studies investigating the role of calcium intake, either from the diet or from supplements, as well as blood concentrations, in relation to the risk of CVD in adults. In vitro and in vivo laboratory studies suggest that calcium may be involved in CVD development through multiple pathways, including blood cholesterol, insulin secretion and sensitivity, vasodilation, inflammatory profile, thrombosis, obesity, and vascular calcification. Several prospective epidemiologic studies have examined how dietary or supplemental calcium intake is associated with CVD incidence or mortality in middle-aged and older adults, and the results are inconsistent. Prospective studies investigating blood concentrations of calcium have also reported mixed results. However, changes in blood calcium concentrations may reflect a disturbed calcium phosphate balance, which is associated with increased risk of CVD. To date there is no randomized clinical trial that has been designed specifically to test the effect of calcium supplementation on the risk of CVD as the primary end point. Existing trials have performed secondary analyses, and most of them have been conducted among postmenopausal women. These trials suggest that calcium supplementation has no effect on CVD development; however, they do not allow a definitive conclusion to be drawn. The average daily intake of calcium is low in many populations; however, the evidence for a potential role of dietary or supplemental calcium in the prevention of CVD remains insufficient and inconclusive. Only large-scale randomized trials designed to investigate the effects of calcium supplementation on CVD events as the primary end point, as well as short-term trials investigating the effect on coronary biomarkers, can provide a definitive answer.     

The Role of Genomic Imprinting of Gsα in the Pathogenesis of Albright Hereditary Osteodystrophy

Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivating mutations of the gene encoding the α-subunit of the G protein G_s. The G_sα gene is a complex gene that uses various alternative promoters and produces various protein products. Recently, it has been shown that this gene is imprinted in a tissue-specific manner. The role of tissue-specific imprinting of G_sα in the pathogenesis of AHO is discussed.