Gene therapy for rheumatoid arthritis: recent advances

The treatment of rheumatoid arthritis (RA) in the last decade has made enormous advances with the use of biological therapies. However, these therapies have serious limitations such as the expense, side-effects, and the requirement for repeated injections, each of which can potentially be obviated by gene therapy. A gene therapy approach for the treatment of RA has the potential to stably deliver a gene product or multiple products in a target-specific, disease-inducible manner. There are many studies investigating gene therapy in RA, the majority of which have been designed to test proof-of-principle in an animal model. With an abundance of animal studies that have established much promise, the field is now at the early stage of moving towards human trials, where patient benefit needs to overshadow associated risks, especially since RA is publicly perceived as a non-life-threatening disease. Here, we provide an overview that focuses on advances in the application of gene therapy to RA over the last five years, including: novel targets and approaches; the viral and non-viral applications most likely to succeed in the clinic; advances in our understanding of the contralateral effect; the latest successes with anti-inflammatory cytokines; and a review of advancements towards clinical trials.     

Chemopreventive Efficacy of Ginger (Zingiber Officinale) in Ethionine Induced Rat Hepatocarcinogenesis

Ginger (Zingiber officinale Rosco) is widely used in foods as a spice all around the world. It has been reported to have antioxidant and anticarcinogenic properties. We investigated the effect of ginger in ethionine induced rat hepatocarcinogenesis. Male Wistar rats were divided into 5 groups: group 1 and 2 served as controls and they received normal rat chow and olive oil respectively. Group 3 was fed with ginger oleoresin dissolved in olive oil at 100 mg/kg body wt. Group 4 was fed with choline deficient diet and 0.1% ethionine in drinking water (CDE diet), and group 5 received ginger with CDE diet. Blood samples were taken from the orbital sinus at 0 and 8 weeks of experiment for the determination of antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase and lipid peroxidation end product, malondialdehyde (MDA). Rats were also killed at 8 weeks for the observation of liver tumor formation. CDE diet induced the formation of liver nodules in rats and increased SOD activity. However, it had no effect on catalase, GPx and MDA levels when compared to both controls at 8 weeks of experiment. When CDE rats were treated with ginger, the formation of liver tumour, SOD activity and MDA level reduced, catalase activity was increased but no change was observed for GPx activity when compared to CDE group. In conclusion, ginger supplementation suppressed liver carcinogenesis by scavenging the free radical formation, and by reducing lipid peroxidation.     

Profile of inflammatory mediators in gestational diabetes mellitus: phenotype and genotype

Citation Gueuvoghlanian‐Silva BY, Torloni MR, Mattar R, de Oliveira LS, Scomparini FB, Nakamura MU, Daher S. Profile of inflammatory mediators in gestational diabetes mellitus: phenotype and genotype. Am J Reprod Immunol 2012; 67: 241–250 Problem Our study aimed to assess in vitro production of IL‐10, IL‐6, TNF‐A, and adiponectin serum levels in pregnant women with and without gestational diabetes mellitus (GDM) and to investigate a possible association between GDM and IL‐10?1082 A>G (rs1800896), IL‐6?174 G>C (rs1800795), TNF‐A?308 G>A (rs1800629), adiponectin +45 T>G (rs2241766), and adiponectin?11377 C>G (rs266729) gene polymorphisms. Method of study This case–control study included 79 women with GDM and 169 healthy controls (C) grouped according to pre‐pregnancy BMI. IL‐10, IL‐6, and TNF‐A culture supernatant and adiponectin serum levels were assessed by ELISA. DNA genotype was performed by PCR‐RFLP. Results Adiponectin levels were significantly higher in C than GDM women, even within the same BMI category. Cytokines levels were similar between the groups. There were no associations between GDM and the analyzed gene polymorphisms. Conclusions Women with GDM have significantly lower adiponectin levels in the third trimester, regardless of BMI.     

Modulation of collagen synthesis and its gene expression in human skin fibroblasts by tocotrienol-rich fraction

Introduction

Skin aging may occur as a result of increased free radicals in the body. Vitamin E, the major chain-breaking antioxidant, prevents propagation of oxidative stress, especially in biological membranes. In this study, the molecular mechanism of tocotrienol-rich fraction (TRF) in preventing oxidative stress-induced skin aging was evaluated by determining the rate of total collagen synthesis and its gene expression in human skin fibroblasts.

Material and methods

Primary culture of human skin fibroblasts was derived from circumcision foreskin of 9 to 12 year-old boys. Fibroblast cells were divided into 5 different treatment groups: untreated control, hydrogen peroxide (H₂O₂)-induced oxidative stress (20 µM H₂O₂ exposure for 2 weeks), TRF treatment, and pre- and post-treatment of TRF to H₂O₂-induced oxidative stress.

Results

Our results showed that H₂O₂-induced oxidative stress decreased the rate of total collagen synthesis and down-regulated COL I and COL III in skin fibroblasts. Pre-treatment of TRF protected against H₂O₂-induced oxidative stress as shown by increase in total collagen synthesis and up-regulation of COL I and COL III (p<0.05) genes. However, similar protective effects against H₂O₂-induced oxidative stress were not observed in the post-treated fibroblasts.

Conclusions

Tocotrienol-rich fraction protects against H₂O₂-induced oxidative stress in human skin fibroblast culture by modulating the expression of COL I and COL III genes with concomitant increase in the rate of total collagen synthesis. These findings may indicate TRF protection against oxidative stress-induced skin aging.     

Prevalence and characteristics of heteroresistant vancomycin-intermediate Staphylococcus aureus bacteremia in a tertiary care center

Infections with S. aureus with heterogeneous intermediate resistance to vancomycin (hVISA) are occurring more frequently. The detection of these infections, their prevalence, clinical characteristics, and significance are controversial. During 2003 and 2004, all blood culture isolates of methicillin-resistant Staphylococcus aureus (264 patients) at the Sheba Medical Center, Tel Hashomer, Israel, were assessed for hVISA by using the Etest macromethod. A total of 16 patients (6%) were positive for hVISA. Resistance to teicoplanin alone and to vancomycin alone using the Etest macromethod was found in 14 and 10 patients, respectively. Standard MICs to vancomycin were between 1 to 4 mg/ml. Most of these isolates (12 of 16 [75%]) would have been missed without specific testing. The median number of bacteremic days was 4. Seven patients had positive blood cultures for more than 5 days. Twelve patients died, and for eight of these the deaths were directly related to hVISA sepsis. We found that hVISA bacteremia was prevalent in our institution, and we suggest seeking hVISA in patients with persistent S. aureus bacteremia.     

The CentriMag Centrifugal Blood Pump as a Benchmark for In Vitro Testing of Hemocompatibility in Implantable Ventricular Assist Devices

Implantable ventricular assist devices (VADs) have proven efficient in advanced heart failure patients as a bridge‐to‐transplant or destination therapy. However, VAD usage often leads to infection, bleeding, and thrombosis, side effects attributable to the damage to blood cells and plasma proteins. Measuring hemolysis alone does not provide sufficient information to understand total blood damage, and research exploring the impact of currently available pumps on a wider range of blood cell types and plasma proteins such as von Willebrand factor (vWF) is required to further our understanding of safer pump design. The extracorporeal CentriMag (Thoratec Corporation, Pleasanton, CA, USA) has a hemolysis profile within published standards of normalized index of hemolysis levels of less than 0.01 g/100 L at 100 mm Hg but the effect on leukocytes, vWF multimers, and platelets is unknown. Here, the CentriMag was tested using bovine blood (n = 15) under constant hemodynamic conditions in comparison with a static control for total blood cell counts, hemolysis, leukocyte death, vWF multimers, microparticles, platelet activation, and apoptosis. The CentriMag decreased the levels of healthy leukocytes (P < 0.006), induced leukocyte microparticles (P < 10^?5), and the level of high molecular weight of vWF multimers was significantly reduced in the CentriMag (P < 10^?5) all compared with the static treatment after 6 h in vitro testing. Despite the leukocyte damage, microparticle formation, and cleavage of vWF multimers, these results show that the CentriMag is a hemocompatible pump which could be used as a standard in blood damage assays to inform the design of new implantable blood pumps.     

Integration of magnetic resonance imaging in characterization of inflammatory breast disorders

Objective

Assess the efficacy of using different imaging modalities aiming at proper characterization of benign and malignant inflammatory breast disorders.