Simvastatin attenuates the endothelial pro-thrombotic shift in saphenous vein grafts induced by Advanced glycation endproducts

Background

Advanced glycation endproducts (AGEs) and its receptors (RAGEs) are heterogeneous signaling proteins associated to diabetes and responsible of endothelial alterations leading to atherosclerosis progression and graft failure. The aim of this study was to investigate the role of statin in reducing AGEs related endothelial damage.

Methods

Endothelial cell(EC) obtained from leftovers of saphenous vein grafts of non-diabetic patients were incubated with AGEs (2 and 20 μM) and subsequently treated with Simvastatin. Neutrophils (PNM) adherence, ROS production and RAGE and peroxisome proliferator-activated receptors-gamma (PPAR-γ) expression were analyzed. As clinical validation of the in vitro findings, ECs of diabetic patients in optimized glycaemic control administered with a 3 weeks Simvastatin regimen were similarly processed.

Results

Simvastatin blunted the rise in PMN adhesion and ROS generation following stimulation of saphenous vein EC culture with AGEs in vitro. This effect was time dependent and was associated to an increase in PPAR-γ induction paralleled by a decrease in RAGEs expression. Parallely, data from diabetic patients administered with Simvastatin showed a similar significant reduction in PNM adhesion and ROS generation. Simvastatin treatment significantly decreased RAGEs expression in ECs from diabetic patients and determined a slight increase in PPAR-γ expression but the latter failed to reach statistical significance. Interference in the function of these two crucial pathways might be at the root of the statin antinflammatory and antithrombotic effect in the context of AGEs-associated damage.

Conclusions

Despite the recently raised warning on the use of statins in the diabetic population, this study elucidates their cornerstone position in endothelial homeostasis of saphenous grafts in patients with controlled diabetes.     

Effects of fibrinogen and platelet supplementation on clot formation and platelet aggregation in blood samples from cardiac surgery patients

Introduction

Bleeding after cardiac surgery may be caused by surgical factors, impaired haemostasis, or a combination of both. Transfusion of blood products is used to improve haemostasis, but little is known about what combination is optimal. We hypothesized that addition of both fibrinogen and platelets to blood samples from cardiac surgery patients would improve clot formation and platelet aggregation to a greater extent than if the components were added separately.

Materials and Methods

Increasing doses of fibrinogen concentrate (+ 0.5, 1.0, and 1.5 g · l^- 1) and/or platelet concentrate (+ 46, 92, and 138 × 10⁹ platelets l^- 1) were added to postoperative blood samples from 15 cardiac surgery patients. Clot formation was assessed with rotational thromboelastometry and platelet aggregation was assessed with multiple-electrode aggregometry before and after addition of the blood products. The effects of the different additives were compared.

Results and Conclusions

Ex vivo supplementation with fibrinogen or platelet concentrate resulted in significantly shortened clotting time and improved clot strength in a dose-dependent manner. Combination of fibrinogen and platelets further improved the clotting time and strength. Platelet supplementation enhanced platelet aggregation in a dose-dependent manner while fibrinogen had no or reducing effect. Combining fibrinogen and platelets improved platelet aggregation less than the use of platelets alone. In conclusion, combined platelet and fibrinogen supplementation of blood samples from cardiac surgery patients had an additive effect on clot formation compared to the individual components, but it resulted in less platelet aggregation than with platelet supplementation alone. These results may have implications for clinical transfusion protocols.     

Chlamydophila pneumoniae phospholipase D (CpPLD) drives Th17 inflammation in human atherosclerosis

Phospholipases are produced from bacterial pathogens causing very different diseases. One of the most intriguing aspects of phospholipases is their potential to interfere with cellular signaling cascades and to modulate the host-immune response. Here, we investigated the role of the innate and acquired immune responses elicited by Chlamydophila pneumoniae phospholipase D (CpPLD) in the pathogenesis of atherosclerosis. We evaluated the cytokine and chemokine production induced by CpPLD in healthy donors' monocytes and in vivo activated T cells specific for CpPLD that infiltrate atherosclerotic lesions of patients with C. pneumoniae antibodies. We also examined the helper function of CpPLD-specific T cells for monocyte matrix metalloproteinase (MMP)-9 and tissue factor (TF) production as well as the CpPLD-induced chemokine expression by human venular endothelial cells (HUVECs). We report here that CpPLD is a TLR4 agonist able to induce the expression of IL-23, IL-6, IL-1β, TGF-β, and CCL-20 in monocytes, as well as CXCL-9, CCL-20, CCL-4, CCL-2, ICAM-1, and VCAM-1 in HUVECs. Plaque-derived T cells produce IL-17 in response to CpPLD. Moreover, CpPLD-specific CD4(+) T lymphocytes display helper function for monocyte MMP-9 and TF production. CpPLD promotes Th17 cell migration through the induction of chemokine secretion and adhesion molecule expression on endothelial cells. These findings indicate that CpPLD is able to drive the expression of IL-23, IL-6, IL-1β, TGF-β, and CCL-20 by monocytes and to elicit a Th17 immune response that plays a key role in the genesis of atherosclerosis.     

Microduplication of 15q13.3 and Xq21.31 in a family with tourette syndrome and comorbidities

Tourette syndrome (TS) is a childhood onset neurodevelopmental disorder. Although it is widely accepted that genetic factors play a significant role in TS pathogenesis the etiology of this disorder is largely unknown. Identification of rare copy number variations (CNVs) as susceptibility factors in several neuropsychiatric disorders such as attention deficit‐hyperactivity disorder (ADHD), autism and schizophrenia, suggests involvement of these rare structural changes also in TS etiology. In a male patient with TS, ADHD, and OCD (obsessive compulsive disorder) we identified two microduplications (at 15q13.3 and Xq21.31) inherited from a mother with subclinical ADHD. The 15q duplication included the CHRNA7 gene; while two genes, PABPC5 and PCDH11X, were within the Xq duplication. The Xq21.31 duplication was present in three brothers with TS including the proband, but not in an unaffected brother, whereas the 15q duplication was present only in the proband and his mother. The structural variations observed in this family may contribute to the observed symptoms, but further studies are necessary to investigate the possible involvement of the described variations in the TS etiology. © 2013 Wiley Periodicals, Inc.     

An unusual case of fatty liver in a patient with desmoid tumor

A desmoid tumor, also known as aggressive fibromatosis, is a rare benign neoplasm that arises from fascial or musculoaponeurotic tissues. It can occur in any anatomical location, most commonly the abdominal wall, shoulder girdle and retroperitoneum. The typical clinical presentation is a painless mass with a slow and progressive invasion of contiguous structures. It is associated with a high local recurrence rate after resection. Many issues regarding the optimal treatment of desmoid tumors remain controversial. Aggressive surgical resection with a wide margin (2-3 cm) remains the gold standard treatment with regard to preserving quality of life. Radiotherapy alone has been shown to be effective for the control of unresectable or recurrent lesions. Desmoid tumors tend to be locally infiltrative, therefore, the fields must be generous to prevent marginal recurrence. The radiation dose appropriate for treating desmoid tumors remains controversial. We present a 25-year-old Caucasian man with local recurrence of a desmoid tumor after repeated surgical resection, treated with radiotherapy. The patient achieved complete tumor regression at 4 mo after radiotherapy, and he is clinically free of disease at 12 mo after the end of treatment, with an acceptable quality of life. The patient developed short bowel syndrome as a complication of second surgical resection. Consequently, radiotherapy might have worsened an already present malabsorption and so led to steatohepatitis.     

Evaluation of 24-locus MIRU-VNTR in extrapulmonary specimens: study from a tertiary centre in Mumbai

Genotyping of Mycobacterium tuberculosis isolates is a useful tool for epidemiological control of tuberculosis (TB) and phylogenetic exploration of the pathogen. There is a lack of information on the discriminatory power of standard 24-locus mycobacterial interspersed repetitive unit (MIRU) - variable number tandem repeats (VNTR) in India, which has the highest tuberculosis (TB) burden worldwide. Therefore, we assessed its utility on 69 M.?tuberculosis (MTB) isolates from patients with extrapulmonary tuberculosis, in comparison to standard insertion sequence (IS) 6110-Restriction fragment length polymorphism (RFLP) fingerprinting and spoligotyping. IS6110-RFLP (HGDI, 0.9987) identified a single cluster of 3 (4.3%) single-copy IS6110 isolates. Spoligotyping showed 69.5% clustering (HGDI, 0.8857). In contrast, MIRU-VNTR analysis identified 69 (100%) unique strains (HGDI, 1.0000). Within the study limits, this observed high discriminatory power suggests that 24-locus MIRU-VNTR genotyping could potentially be used to study long-term transmission of MTB infection in Mumbai. Moreover, high congruence between the MIRU-VNTR-based and spoligotyping-based strain groupings suggests that CAS, EAI and Beijing are the predominant strain lineages in the Mumbai TB patient population. The Beijing lineage isolates were found to be more significantly associated with multi-drug resistance (p?相似文献