The effect of per os colchicine administration in combination with fenofibrate and N-acetylcysteine on triglyceride levels and the development of atherosclerotic lesions in cholesterol-fed rabbits.

OBJECTIVE: Atherosclerosis is a chronic inflammatory disease promoted by pro-inflammatory cytokines produced by NOD-, LRR- and pyrin domain-containing protein 3 (NLRP 3) inflammasome. Colchicine is an anti-inflammatory agent that inhibits inflammasome's action and stabilizes atherosclerotic lesions. N-acetylcysteine (NAC) reduces low-density lipoprotein (LDL) oxidation, metalloproteinase levels, and foam cell count and volume. Fenofibrate also has antioxidant, anti-inflammatory, and anticoagulant properties while also having a beneficial effect on the vasomotor function of the endothelium. The purpose of this study is to investigate the effect of per os colchicine administration in combination with fenofibrate and NAC on triglyceride levels and the development of atherosclerotic lesions in cholesterol-fed rabbits. MATERIALS AND METHODS: Twenty-eight male, 2 months old New Zealand White rabbits were separated into four groups and were fed with different types of diet for 7 weeks: standard, cholesterol 1% w/w, cholesterol 1% w/w plus colchicine 2 mg/kg body weight plus 250 mg/kg body weight/day fenofibrate, and cholesterol 1% w/w plus colchicine 2 mg/kg body weight plus 15 mg/kg body weight/day NAC. Blood samples were drawn from all animals. Lipid profiles were assessed, and interleukin 6 (IL-6) measurements were performed using an enzyme-linked immunosorbent assay (ELISA) kit. Histologic examination was performed on aorta specimens stained with eosin and hematoxylin. Aortic intimal thickness was evaluated using image analysis. RESULTS: Colchicine administration in combination with fenofibrate or NAC statistically significantly reduced the extent of atherosclerotic lesions in aortic preparations. Co-administration of colchicine with NAC has a stronger anti-atherogenic effect than the colchicine plus fenofibrate regimen. Triglerycide levels were decreased in the colchicine plus fenofibrate group and the colchicine plus NAC group at the end of the experiment (p < 0.05), whereas the Cholesterol group had increased levels. A favorable significant lower concentration of IL-6 was detected in the colchicine plus NAC group vs. the other groups. CONCLUSIONS: In an experimental rabbit model, it appears that colchicine statistically significantly reduces the development of atherosclerosis of the aorta, especially in combination with NAC. Colchicine, as an NLRP3 inflammasome inhibitor, and NAC, as an agent that directly targets IL-6 signaling, can reduce the inflammatory risk. Fenofibrate enhances the attenuating role of colchicine on triglyceride levels. Clinical studies should investigate whether similar effects can be observed in humans.

Intravenous lipid emulsion as an antidote in clinical toxicology: a systematic review.

OBJECTIVE: Intravenous lipid emulsions (ILE) were developed many decades ago to supply nutritional requirements to patients unable to obtain adequate enteral nutrition. The utility of ILE was extended to therapeutics, facilitating the delivery of drugs. More recently, the potential for ILE to act as an antidote for inversion of drug toxicity has been recognized. This review aims to summarize the literature on ILE therapy as an antidote. Suggested mechanisms of action, safety profile, and recommendations on the administration of ILE in cases of drug intoxication are highlighted. MATERIALS AND METHODS: A complete literature survey was performed using the PubMed database search to collect available information regarding mechanisms of ILE action as an antidote, ILE administration for drug toxicity, and presentation of adverse events. RESULTS: A total of 102 studies met the selection criteria for inclusion in the review. Mainly used for local anesthetics toxicity, ILE therapy has been expanded in clinical toxicology involving overdose treatment of drugs other than local anesthetics. Partitioning in a lipid phase of fat droplets is a mechanism named the lipid sink phenomenon that has primarily been described to explain this action of ILE and remains the most widely accepted. At the same time, recent research has also revealed several molecular mechanisms that may contribute to ILE efficacy. CONCLUSIONS: ILE therapy comprises a recognized approach in clinical toxicology. Due to the lack of randomized clinical trials, recommendations on administration are based on animal studies and published cases. Thus, the constantly increased knowledge about ILE therapy supports the need for a detailed appraisal.

Changes in serum leptin levels as well as sICAM-1 and sVCAM-1 soluble adhesion molecules during carotid endarterectomy.

OBJECTIVE: Leptin is an adipokine, known to be associated with oxidative stress, inflammation, and atherogenesis. Leptin plays an essential role in atheromatosis-associated inflammatory cascade through stimulation of inflammatory mediators such as soluble intracellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1). However, little is known about this association in patients with atherosclerosis and severe internal carotid artery (ICA) stenosis undergoing carotid endarterectomy (CEA). Our objective was to evaluate the variations of serum leptin levels, as well as sICAM-1 and sVCAM-1 levels in these patients during the process of CEA and 24 hours postoperatively. PATIENTS AND METHODS: The study group enrolled 50 patients undergoing CEA for ICA stenosis (> 70%). Serum leptin, sICAM-1 and sVCAM-1 plasma concentration measurements were performed at 4 distinct time points: before clamping of the ICA, 30 minutes after clamping of the ICA, 60 minutes after declamping of ICA and 24 hours postoperatively. RESULTS: Leptin was significantly decreased during CEA, but an overshooting in its levels was observed at 24 hours after the operation. Both sICAM-1 and sVCAM-1 initially followed the pattern of leptin changes but after completing CEA and up to 24 hours postoperatively a steep increase in their levels was not established. sVCAM-1 and sICAM-1 correlated with indices of oxidative stress at peak inflammatory burden. CONCLUSIONS: Leptin is a circulating marker of carotid atherosclerosis. Oxidative stress and expression of sVCAM-1 and sICAM-1 on vascular endothelial cells are key features in the pathophysiological process of atherosclerosis.

Cardiac allograft vasculopathy after heart transplantation: current prevention and treatment strategies.

OBJECTIVE: Cardiac allograft vasculopathy (CAV) is a leading cause of mortality in heart transplantation patients. Despite optimal immunosuppression therapy, the rate of CAV post-transplantation remains high. In this review, we gathered all recent studies as well as experimental evidence focusing on the prevention and treatment strategies regarding CAV after heart transplantation. MATERIALS AND METHODS: A complete literature survey was performed using the PubMed database search to gather available information regarding prevention and treatment strategies of CAV after heart transplantation. RESULTS: Several non-immune and immune factors have been linked to CAV such as ischemic reperfusion injury, metabolic disorders, cytomegalovirus infection, coronary endothelial dysfunction, injury and inflammation respectively. Serial coronary angiography combined with intravascular ultrasound is currently the method of choice for detecting early disease. Biomarkers and noninvasive imaging can also assist in the early identification of CAV. Treatment strategies such as mammalian target of rapamycin inhibitors proceed to grow, but prevention remains the objective. CONCLUSIONS: Early detection is the key to therapy management. It enables early identification and diagnosis of patients with CAV, who would gain the most from prompt treatment. Further investigation is needed to elucidate the multifactorial pathophysiological process of CAV, develop detection methods and find treatments that prevent or slow disease progression.

Association of brain natriuretic peptide and adrenomedullin plasma levels with left ventricular filling pressures in end-stage renal disease patients on hemodialysis.

OBJECTIVE: Adrenomedullin (ADM) and brain natriuretic peptide (BNP) are known to be associated with elevated left ventricular filling pressures. However, little is known about this association in hemodialysis (HD) patients with preserved left ventricular ejection fraction (LVEF). Our objective was to evaluate the potential association between E/e' ratio and plasma levels of BNP and ADM in end-stage renal disease (ESRD) patients with preserved LVEF undergoing chronic hemodialysis. PATIENTS AND METHODS: The study group enrolled 62 ESRD patients treated with hemodialysis three times weekly. BNP and ADM plasma concentration measurements and echocardiographic examination were performed 30 minutes after hemodialysis. E/e' ratio, evaluated by Tissue Doppler imaging and measured at the basal septum, was used as a surrogate marker for assessing left ventricular filling pressures. RESULTS: The mean age of patients was 62 ± 25 years. The mean BNP and ADM values after hemodialysis were 0.40 ± 6.73 ng/ml and 0.06 ± 2.12 ng/ml, respectively. Elderly patients with hypertrophied left ventricles and larger left atria displayed higher E/e' values. BNP (r = 0.324. p = 0.018) and ADM (r = 0.319, p = 0.042) plasma levels were positively and significantly associated with E/e΄. Multivariate regression analysis including BNP, ADM, age, hemodialysis duration, left ventricular end-systolic volume index, LVEF, left ventricular mass index and left atrium volume index, revealed that ADM (p-value 0.025) but not BNP levels, were independently associated with the E/e' ratio. CONCLUSIONS: ADM, but not BNP, was independently associated with septal E/e' in HD patients with preserved LVEF. ADM plasma levels can be used as a surrogate index to assess left ventricular filling pressures in HD patients.

Tumor potential in rat wounds after short- and long-term administration of platelet-rich plasma: an update.

Comment on: Omar NN, et al. Tumor potential in rat wounds after short- and long-term administration of platelet-rich plasma. J Biol Regul Homeost Agents. 2017 Oct-Dec;31(4):889-899. Platelet-Rich Plasma (PRP) is a promising concentrate. But are there any disadvantages or contraindications regarding its application? Is the use of PRP indicated in wounds of patients undergoing resection for cancer. The presence of growth factors could promote tumor proliferation and recurrence. It is of the utmost importance to recognize any possible contraindication before we call it safe. The role of PRP in tumorigenicity deserves further experimental investigation and large-scale prospective randomized clinical trials.

The complex crosstalk between inflammatory cytokines and ventricular arrhythmias.

The network of cytokines consists one of the most extensively studied signaling systems of human body. Cytokines appear to modulate pathogenesis and progress of many different diseases in the human body, particularly in regards to cardiovascular system. However, their effects on the electrical system of the heart has been neglected. Over the past decade, attemps to understand this relationship led to the uncovering of the direct and indirect effects of cytokines on action potential propagation and cell depolarization. This relationship has been depicted in clinical practice as serum levels of cytokines are increasingly associated with prevalence of ventricular arrhythmias either isolated or secondary to either a heart condition or a systemic auto-immune disease. Thus, they present an appealing potential as a biomarker for prediction of arrhythmia generation, as well as the ourtcome of electrophysiological interventions.

Cryoablation for atrial fibrillation and antiarrhythmic drug pretreatment: a single referral center experience.

OBJECTIVE: Pulmonary vein isolation (PVI) ablation has emerged as the gold standard of ablative strategies to treat medically refractory paroxysmal and persistent atrial fibrillation (AF). Regardless of the superiority of catheter ablation based on PVI over antiarrhythmic drug therapy, recurrence rates of AF remain higher than desired. PVI via cryoablation has rapidly become a mainstream treatment for AF, due to its effectiveness and fast learning curve. Our objective was to assess the safety and efficacy of cryoablation in a single referral center. PATIENTS AND METHODS: This is a retrospective analysis of results after cryoablation treatment of AF over three years. 146 patients with AF underwent a cryoablation procedure in our clinical center and were followed-up for three years after the procedure. All patients received cryoablation of the pulmonary veins, although concomitant procedures were performed in 6 patients (re-ablation), including radiofrequency and cryoablation. RESULTS: Cryoablation was clinically successful in 90.83% of the patients with paroxysmal AF and 60% of those with persistent AF. The clinical success of cryoablation was correlated with pretreatment with amiodarone and in the case of re-ablation. Concerning postoperative complications, major bleeding was correlated with female gender, treatment with rivaroxaban and amiodarone. CONCLUSIONS: Among large trials, freedom from recurrent AF is about 65% with follow-up limited to 1 to 2 years. PVI via balloon cryoablation is a safe and efficient guideline-based treatment for AF, producing a durable event-free result in most patients out to 3 years with better outcomes than previously reported.

Targeting histone deacetylases in endometrial cancer: a paradigm-shifting therapeutic strategy?

OBJECTIVE: Endometrial cancer is increasingly prevalent in western societies and affects mainly postmenopausal women; notably incidence rates have been rising by 1.9% per year on average since 2005. Although the early-stage endometrial cancer can be effectively managed with surgery, more advanced stages of the disease require multimodality treatment with varying results. In recent years, endometrial cancer has been extensively studied at the molecular level in an attempt to develop effective therapies. Recently, a family of compounds that alter epigenetic expression, namely histone deacetylase inhibitors, have shown promise as possible therapeutic agents in endometrial cancer. The present review aims to discuss the therapeutic potential of these agents. MATERIALS AND METHODS: This literature review was performed using the MEDLINE database; the search terms histone, deacetylase, inhibitors, endometrial, targeted therapies for endometrial cancer were employed to identify relevant studies. We only reviewed English language publications and also considered studies that were not entirely focused on endometrial cancer. Ultimately, sixty-four articles published until January 2018 were incorporated into our review. RESULTS: Studies in cell cultures have demonstrated that histone deacetylase inhibitors exert their antineoplastic activity by promoting expression of p21WAF1 and p27KIP1, cyclin-dependent kinase inhibitors, that have important roles in cell cycle regulation; importantly, the transcription of specific genes (e.g., E-cadherin, PTEN) that are commonly silenced in endometrial cancer is also enhanced. In addition to these abstracts effects, novel compounds with histone deacetylase inhibitor activity (e.g., scriptaid, trichostatin, entinostat) have also demonstrated significant antineoplastic activity both in vitro and in vivo, by liming tumor growth, inducing apoptosis, inhibiting angiogenesis and potentiating the effects of chemotherapy. CONCLUSIONS: The applications of histone deacetylase inhibitors in endometrial cancer appear promising; nonetheless, additional trials are necessary to establish the therapeutic role, clinical utility, and safety of these promising compounds.

Successful combined surgical approach in a rare case of retrotracheal goitre in a patient with anatomical impediments.

Diving goitres can descend the cervical region expanding directly into the thoracic cavity. In most cases, diving goitres extend into the anterosuperior compartment, but they may also extend behind the trachea. We herein present a case of a male patient with retrotracheal goitre and history of left thyroid lobectomy and median sternotomy for thoracic aortic aneurysm repair with graft placement. After detailed preoperative evaluation, the patient underwent surgical resection of the mass through a combined approach; the existing cervical incision and a right posterolateral mini-thoracotomy. The postoperative course of the patient was uncomplicated. One year after surgery, the patient is asymptomatic and disease-free. (Folia Morphol 2018; 77, 1: 166-169).

The role of prasugrel in the management of acute coronary syndromes: a systematic review.

OBJECTIVE: Dual antiplatelet therapy (DAPT) is the treatment of choice in the medical management of patients with acute coronary syndrome (ACS). The combination of aspirin and a P2Y12 inhibitor in patients who receive a coronary stent reduces the rate of stent thrombosis and the rates of major adverse cardiovascular events. However, patients with acute coronary syndrome remain at risk of recurrent cardiovascular events despite the advance of medical therapy. The limitations of clopidogrel with variable antiplatelet effects and delayed onset of action are well established and lead to the development of newer P2Y12 inhibitors. Prasugrel is a selective adenosine diphosphate (ADP) receptor antagonist indicated for use in patients with ACS. Prasugrel provides greater inhibition of platelet aggregation than clopidogrel and has a rapid onset of action. We have conducted a systematic review to retrieve current evidence regarding the role of prasugrel in the management of ACS. Evidence comparing prasugrel, clopidogrel, and ticagrelor remain scant. MATERIALS AND METHODS: A complete literature survey was performed using PubMed database search to gather available information regarding management of acute coronary syndromes and prasugrel. An explorative comparison of the safety and efficacy of prasugrel, clopidogrel, and ticagrelor was also conducted. RESULTS: Prasugrel and ticagrelor are more efficacious than clopidogrel in reducing the occurrence of non-fatal myocardial infarction, stroke, or cardiovascular (CV) death but they have also an increased risk of major bleeding in comparison to clopidogrel. CONCLUSIONS: Prasugrel and ticagrelor are today the recommended first-line agents in patients with ACS. The estimation of which drug is superior over the other cannot be reliably established from the current trials.

Large thoracic tumour without superior vena cava syndrome.

A 62-year-old male with long-standing smoking history presented with haemoptysis. Plain chest X-ray showed abnormal findings proximate to the right pulmonary hilum. Bronchoscopy revealed a fragile exophytic tumour of the right wall of the lower third of the trachea, infiltrating the right main bronchus (75% stenosis) and the right upper lobar bronchus (near total occlusion). Contrast-enhanced chest computed tomography demonstrated a 7.2 × 4.9 cm tumour contiguous to the above-mentioned structures, mediastinal lymph node pathology, and a vessel coursing inferiorly to the left of the aortic arch and anterior to the left hilum. Despite the tumour constricting the right superior vena cava (SVC), no signs of SVC syndrome were present. In this case, the patient does not present with SVC syndrome, as expected due to the constriction of the (right) SVC caused by the tumour, since head and neck veins drain through the persistent left superior vena cava (PLSVC). PLSVC is the most common thoracic venous anomaly with an incidence of 0.3% to 0.5% of the general population and it is a congenital anomaly caused by the failure of the left anterior cardinal vein to regress and to consequently form the ligament of Marshall during foetal development. It is associated with absence of the left brachiocephalic vein and in 10% to 20% of cases the right SVC is absent. Two potential draining points of the PLSVC have been previously reported. In the majority of cases PLSVC drains directly into the coronary sinus, but less frequently it drains into the left atrium or the left superior pulmonary vein (LSPV). In cases where the PLSVC drains into the coronary sinus, congenital heart defects are rare. The patient usually remains asymptomatic and PLSVC is an incidental finding during radiographic imaging or medical procedures. When the PLSVC drains into the left atrium or the LSPV, a right-to-left shunt is formed; a condition usually asymptomatic. In some reported cases this PLSVC variant presents with persistent, unexplained hypoxia or cyanosis and embolisation causing recurrent transient ischaemic attacks and/or cerebral abscesses. This PLSVC variant is more often associated with absence of the right SVC and congenital heart abnormalities.