Statin therapy protects against abdominal aortic aneurysms by inducing the accumulation of regulatory T cells in ApoE−/− mice

Journal of Molecular Medicine - CD4+CD25+ regulatory T cells (Tregs) have been shown to protect against abdominal aortic aneurysm (AAA) progression. Statins have immunomodulatory properties, and...     

Transforming growth factor-β and abdominal aortic aneurysms

Abdominal aortic aneurysms (AAAs) are common problems in aged people which can be associated with severe complications including aortic rupture and death. Transforming growth factor-β (TGFβ) has been implicated as causative in the development of thoracic aortic aneurysms (TAAs). In contrast, current evidence suggests TGFβ inhibits AAA development. Polymorphisms in the TGFβ signaling components are associated with AAA in some human population studies. In experimental animals TGFβ protects against AAA formation, progression and rupture. In animal models of AAA TGFβ decreases aortic inflammatory cell infiltration, extracellular matrix degradation, and vascular smooth muscle cell apoptosis, all factors implicated in AAA pathogenesis. The TGFβ signaling pathway may provide a therapeutic target for AAA although better clarity is needed regarding the distinct roles of TGFβ in TAA and AAA.     

Induction of antigen-specific tolerance through hematopoietic stem cell-mediated gene therapy: The future for therapy of autoimmune disease?

Based on the principle that immune ablation followed by HSC-mediated recovery purges disease-causing leukocytes to interrupt autoimmune disease progression, hematopoietic stem cell transplantation (HSCT) has been increasingly used as a treatment for severe autoimmune diseases. Despite clinically-relevant outcomes, HSCT is associated with serious iatrogenic risks and is suitable only for the most serious and intractable diseases. A further limitation of autologous HSCT is that relapse rates can be high, suggesting disease-causing leukocytes are incompletely purged or the environmental and genetic determinants that drive disease remain active. Incorporation of antigen-specific tolerance approaches that synergise with autologous HSCT could reduce or prevent relapse. Further, by reducing the requirement for highly toxic immune-ablation and instead relying on antigen-specific tolerance, the clinical utility of HSCT could be significantly diversified. Substantial progress has been made exploring HSCT-mediated induction of antigen-specific tolerance in animal models but studies have focussed on primarily on prevention of autoimmune diseases. However, as diagnosis of autoimmune disease is often not made until autoimmune disease is well developed and populations of autoantigen-specific pathogenic effector and memory T cells have become well established, immunotherapies must be developed to address effector and memory T-cell responses which have traditionally been considered the key impediment to immunotherapy. Here, focusing on T-cell mediated autoimmune diseases we review progress made in antigen-specific immunotherapy using HSCT-mediated approaches, induction of tolerance in effector and memory T cells and the challenges for progression and clinical application of antigen-specific ‘tolerogenic’ HSCT therapy.     

The effect of angulation in abdominal aortic aneurysms: fluid–structure interaction simulations of idealized geometries

Abdominal aortic aneurysm (AAA) represents a degenerative disease process of the abdominal aorta that results in dilation and permanent remodeling of the arterial wall. A fluid structure interaction (FSI) parametric study was conducted to evaluate the progression of aneurysmal disease and its possible implications on risk of rupture. Two parametric studies were conducted using (i) the iliac bifurcation angle and (ii) the AAA neck angulation. Idealized streamlined AAA geometries were employed. The simulations were carried out using both isotropic and anisotropic wall material models. The parameters were based on CT scans measurements obtained from a population of patients. The results indicate that the peak wall stresses increased with increasing iliac and neck inlet angles. Wall shear stress (WSS) and fluid pressure were analyzed and correlated with the wall stresses for both sets of studies. An adaptation response of a temporary reduction of the peak wall stresses seem to correlate to a certain extent with increasing iliac angles. For the neck angulation studies it appears that a breakdown from symmetric vortices at the AAA inlet into a single larger vortex significantly increases the wall stress. Our parametric FSI study demonstrates the adaptation response during aneurysmal disease progression and its possible effects on the AAA risk of rupture. This dependence on geometric parameters of the AAA can be used as an additional diagnostic tool to help clinicians reach informed decisions in establishing whether a risky surgical intervention is warranted.     

Elastin-laminin receptor and abdominal aortic aneurysms. New subject to study? A review.

Abdominal aortic aneurysms and their management remain a significant health problem that is likely to assume greater importance with the expansion of the elderly population. Elastin fibres degradation and extracellular matrix remodelling seems to be the basic process in aneurysm formation. Recent investigations revealed the principal role of elastin-laminin receptor in extracellular matrix remodelling in aging and atherosclerosis. The correlation between events observed in animal aneurysm models, human aneurysms and in experiments on elastin-laminin receptor properties was discussed to propose the hypothesis about the role of elastin peptides and elastin-laminin receptor in aortic aneurysm formation.     

Mycobacterium bovis abdominal aortic and femoral artery aneurysms following intravesical bacillus Calmette–Guérin therapy for bladder cancer

BackgroundInfectious complications of intravesical bacillus Calmette–Guérin (BCG) therapy are rare, but these have included a handful of cases of mycotic aneurysm.Methods and ResultsWe present the case of a patient with a ruptured abdominal aortic aneurysm and a femoral artery aneurysm who had previously received intravesical BCG therapy for bladder carcinoma. Histopathologic examination of resected tissue revealed numerous acid-fast bacilli, and subsequent mycobacterial culture of blood and resected tissue revealed BCG strain Mycobacterium bovis.ConclusionsClinicians should be aware of the possible extravesical complications, albeit rare, of BCG therapy. Therapy should consist of combined medical and surgical management.     

Prognostic value of tissue factor in patients with abdominal aortic and iliac arterial aneurysms – preliminary study

Introduction

The decision on the time and choice of strategy of treatment of abdominal aortic aneurysm must be especially carefully balanced. The aim of the study was to evaluate the tissue factor (TF) plasma level as a potential factor useful in anticipation of abdominal aortic aneurysm and/or iliac arterial aneurysm via comparison of plasma TF level in patients with ruptured and non-ruptured aneurysms.

Material and methods

The study included 33 patients with aneurysm (17 operated on electively because of non-ruptured aneurysm and 16 operated on emergently due to ruptured aneurysm), 33 claudicant patients with atherosclerosis of the abdominal aorta and iliac arteries with normal diameter of arteries, and 30 healthy controls. Plasma TF level was assessed by ELISA method using the IMUBIND Tissue Factor ELISA Kit (American Diagnostica Inc.).

Results

The study showed an increased TF level in patients with aneurysm (134 ±54 pg/ml) and in patients with atherosclerosis without concomitant aneurysm (91 ±30 pg/ml) in comparison with the control group (62 ±20 pg/ml), respectively p < 0.001 and p = 0.008. A significantly higher TF plasma level was observed in patients with ruptured abdominal aortic aneurysms (160 ±57 pg/ml) as compared to patients with non-ruptured aortic aneurysms (109 ±39 pg/ml) or peripheral arterial occlusive disease (91 ±30 pg/ml), respectively p < 0.001 and p < 0.001. The difference in TF level between the group with non-ruptured aortic aneurysms (109 ±39 pg/ml) and the patients with atherosclerosis without aneurysm (91 ±30 pg/ml) was not statistically significant.

Conclusions

No difference in TF level between patients with non-ruptured AAA/IAA and patients with aortic and iliac atherosclerosis without aneurysm indicates that an increased TF plasma level is not specific for any of the above-mentioned vascular pathologies.     

Antithrombotic therapy – predictor of early and long-term bleeding complications after transcatheter aortic valve implantation

Introduction

Dual antiplatelet therapy (DAPT) – aspirin and clopidogrel – is recommended after transcatheter aortic valve implantation (TAVI) without an evidence base. The main aim of the study was to estimate the impact of antithrombotic therapy on early and late bleeding. Moreover, we assessed the impact of patients’ characteristics on early bleeding and the influence of bleeding on prognosis.

Material and methods

Between 2009 and 2011, 83 consecutive TAVI patients, age 81.1 ±7.2 years, were included. Bleeding complications were defined by the Valve Academic Research Consortium (VARC) scale. The median follow-up was 12 ±15.5 months (range: 1 to 23) and included 68 (81.9%) patients.

Results

Early bleeding occurred in 51 (61.4%) patients. Vitamin K antagonists (VKA) pre-TAVI (p = 0.001) and VKA + clopidogrel early post-TAVI (p = 0.04) were the safest therapies; in comparison to the safest one, peri-procedural DAPT (p = 0.002; p = 0.05) or triple anticoagulant therapy (TAT) (p = 0.003, p = 0.05) increased the risk for early bleeding. Predictors for early bleeding were: clopidogrel pre-TAVI (OR: 4.43, 95% CI: 1.02–19.24, p = 0.04), preceding percutaneous coronary intervention (PCI) (10.08, OR: 95% CI: 1.12–90.56, p = 0.04), anemia (OR: 4.00, 95% CI: 1.32–12.15, p = 0.01), age > 85 years (OR: 5.96, 95% CI: 1.47–24.13, p = 0.01), body mass index (BMI) (OR: 0.86, 95% CI: 0.74–0.99, p = 0.04). Late bleeding occurred in 35 patients (51.4%) on combined therapy, and none on VKA or clopidogrel monotherapy (p = 0.04). Bleeding complications did not worsen the survival.

Conclusions

This study seems to suggest that advanced age, BMI, and a history of anemia increased the risk for early bleeding after TAVI. Clopidogrel pre-TAVI should be avoided; therefore, time of preceding PCI should take into account discontinuation of clopidogrel in the pre-TAVI period. Vitamin K antagonists with clopidogrel seems to be the safest therapy in the early post-TAVI period, similarly as VKA/clopidogrel monotherapy in long-term prophylaxis.     

Do the emotional side-effects of hormonal contraceptives come from pharmacologic or psychological mechanisms?

Hormonal preparations have become one of the most popular methods used for controlling fertility. The literature over the last 40 years continues to reveal how their numerous side effects negatively impact many users and even society at large. Three large cohort trials were the first to demonstrate, on a grand scale, certain emotional and behavioral associations with contraceptive use. Current contraceptive use was associated with an increase rate in depression, divorce, tranquilizer use, sexual dysfunction, and suicide and other violent and accidental deaths. Despite the advent of more "user friendly" contraceptives, the discontinuation rate secondary to side effects has changed little through the years. While in rare cases hormonal preparations can be deadly to the user, there is substantial evidence that their negative effect issues more from their emotional and behavioral properties. This paper reviews the results of over seven studies which further characterize these prominent associations, particularly with hormonal contraception, in an attempt to demonstrate their association with the intrinsic pharmacologic properties of hormonal preparations. Hormonal contraceptive users, in contrast with non users, were found to have higher rates of depression, anxiety, fatigue, neurotic symptoms, sexual disturbances, compulsion, anger, and negative menstrual effects. The question of whether the association of these maladies is directly due to the effect of taking exogenous hormones versus the psychological impact of the contraceptive behavior itself had yet to be studied. Seven small randomized-controlled trials were found in a review of the literature which studied this hypothesis in a direct way. They do not support the origination of these side effects being from the pharmacological properties of hormones. No association was found between hormone levels and emotional functioning in females. Psychiatric evaluations among IUD and oral contraceptive pill (OCP) users reveal no significant differences. Women who were given an OCP placebo experienced a similar side effect profile of OCP users. Different hormonal concentrations and combinations made no significant difference in the side effect profile. A study of women who were given either "weak female hormones" or a placebo failed to duplicate the side effect profile found in all of the other studies where the hormones were labeled as contraceptives. The evidence suggests that most of the side effects of hormonal contraception are a result of a psychological response to the practice of contraception. More study is warranted to further understand this psychological phenomenon, especially now that an effective non-contraceptive method of fertility regulation and more reliable psychological instruments are available. Furthermore, it is reasonable to hypothesize, given the present data, that contraceptive activity itself is inherently damaging to women.     

Targeted therapy of melanoma: fact or fiction?

Advanced malignant melanoma is incurable by the current means of therapy. Traditional morphological classification (nodular melanoma, lentigo maligna melanoma, nevoid melanoma etc.) does not have any significant prognostic or predictive impact. Recent advances in molecular pathogenesis and the availability of targeted therapies have produced several positive results. In the near future, the main challenge for pathologists, geneticists and oncologists will be the identification of accurate therapeutic targets, as well as mechanisms of resistance, in melanoma in the particular patient in care.     

Natural therapy instead of chemistry? Probiotics in gastroenterology

Probiotics are living microorganisms that upon ingestion exert health benefits. The impact of probiotics on gut flora represents a new and interesting therapeutic approach in a number of diseases of the gastrointestinal tract. According to actual publications and guidelines of medical societies, the clinical relevance of probiotics can be described as follows: (a) In the case of ulcerative colitis, available data demonstrate benefits of probiotic therapy. (b) The available data regarding pouchitis are limited, but the therapeutic effect seems to be excellent. (c) In the case of Crohn's disease, the role of probiotics is not clearly defined, thus the results of new trials have to be awaited before probiotic therapy is recommended. (d) Further indications such as antibiotic-associated diarrhea, acute pancreatitis or irritable bowel syndrome have been reported recently. The results of these clinical trials have been encouraging, but they often included only a small number of patients and therefore a clear-cut assessment seems difficult at the moment.