Role of interleukins in heart failure with reduced ejection fraction.

Heart failure (HF) is the leading cause of morbidity and mortality in developed countries, and it is the primary cause of mortality in the elderly worldwide. The processes of inflammatory response activation, production and release of pro-inflammatory cytokines, activation of the complement system, synthesis of autoantibodies, and overexpression of Class II major histocompatibility complex molecules contribute to the HF development and progression. High levels of circulating cytokines correlate with the severity of HF, measured with the use of New York Heart Association's classification, and prognosis of the disease. In HF, there is an imbalance between pro-inflammatory and anti-inflammatory cytokines. Concentrations of several interleukins are increased in HF, including IL-1ß, IL-6, IL-8, IL-9, IL-10, IL-13, IL-17, and IL-18, whereas the levels of IL-5, IL-7, or IL-33 are down-regulated. Concentrations of inflammatory mediators are associated with cardiac function and can be HF markers and predictors of adverse outcomes or mortality. This review presents the role of interleukins, which contribute to the HF initiation and progression, the importance of their pathways in transition from myocardial injury to HF, and the role of interleukins as markers of disease severity and outcome predictors.

The concentration of interleukin-33 in heart failure with reduced ejection fraction.

OBJECTIVE: Despite several improvements in the management of heart failure (HF), it is still an incurable and a progressive disease. Several trials demonstrated that the process of inflammation may be responsible for initiation and progression of HF. The aim of the present study was to investigate the role of interleukin-33 (IL-33) in the pathogenesis of HF and to assess whether disease etiology and course of the disease affect the expression of cytokines. METHODS: The study included 155 (106 male and 49 female) patients with systolic HF with a mean left ventricle ejection fraction of 32.13+-12.8% and 60 (36 male and 24 female) healthy individuals. IL-33 concentrations were evaluated using enzyme-linked immunosorbent assay. RESULTS: The concentration of IL-33 was statistically significantly lower in patients with HF than in healthy subjects, 16.91 (0-81.00) pg/mL and 92.51 (33.61-439.61) pg/mL, respectively. Patients with HF with ischemic etiology had lower concentration of IL-33 (10.75 pg/mL) than subjects with HF with non-ischemic etiology (21.05 pg/mL). Patients with stable HF (10.46 pg/mL) had lower IL-33 levels than those with unstable HF (19.02 pg/mL). CONCLUSION: The concentrations of IL-33 were lower in patients with HF than in healthy controls, which may play an important role of above cytokine in HF development and progression. In addition, interleukin concentrations varied depending on the etiology and severity of the course of the disease.

Apoptosis in Primary Hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is defined by inappropriate elevation of parathormone, caused by parathyroid hyperplasia, also known as multi-gland disease (MGD), parathyroid adenoma (PA), or parathyroid carcinoma (PC). Although several studies have already been conducted, there is a lack of a definite diagnostic marker, which could unambiguously distinguish MGD from PA or PC. The accurate and prompt diagnosis has the key meaning for effective treatment and follow-up. This review paper presents the role of apoptosis in PHPT. The comparison of the expression of Fas, TRAIL, BCL-2 family members, p53 in MGD, PA, and PC, among others, was described. The expression of described factors varies among proliferative lesions of parathyroid gland; therefore, these could serve as additional markers to assist in the diagnosis.

Oxidative stress in proliferative lesions of parathyroid gland.

BACKGROUND: Primary hyperparathyroidism (PHPT) is one of the most common endocrine disorders and defined as excessive secretion of parathormone. PHPT is a risk factor of several cardiovascular diseases, which could be caused by alterations in oxidant-antioxidant balance. MATERIALS AND METHODS: Blood serum collected from 52 consecutive patients with PHPT treated surgically constituted our study material, whereas 36 healthy volunteers were our control group. Oxidative stress was evaluated in both patients and control subjects by assessment of malondialdehyde (MDA) and lipid hydroperoxides (LHP). Antioxidants were evaluated by the measurement of superoxide dismutase (SOD), ceruloplasmin (CER), catalase (CAT), sulfhydryl (SH) groups, glutathione (GSH), glutathione peroxidase (GSH-Px), glutathione transferase activity (GST) and glutathione reductase (GR). Moreover total antioxidant capacity (TAC) and total oxidative status (TOS) were measured and oxidative stress index (OSI) was calculated. RESULTS: OSI was increased in patients with PHPT when compared to normal controls, whereas TAC was lower in PHPT. The levels of CER, MnSOD, GR, SH groups and MDA were significantly decreased in PHPT. The levels of serum LHP, catalase and SOD were significantly higher in patients with PHPT than in healthy patients. The erythrocyte CAT activity and GST were significantly increased in patients after parathyroidectomy. The erythrocyte GR and GPx were up-regulated postoperatively, whereas SOD activity decreased. CONCLUSIONS: In PHPT there are several alterations in the balance between the production of reactive oxygen species and antioxidant defense system.

Notch and its oncogenic activity in human malignancies.

BACKGROUND: Increasing evidence has demonstrated that Notch signaling is deregulated in human hematological malignancies and solid tumors. This signaling has a protumorigenic effect but may also act as a tumor suppressor. How induction of a single pathway gives rise to the opposite effects in different cell types is still unknown. METHODS: This review article includes available data from peer-reviewed publications associated with the role of Notch signaling during cancer pathogenesis. RESULTS: Numerous reports have indicated that alterations in Notch signaling and its oncogenic activity were originally associated with the pathogenesis of T­cell acute lymphoblastic leukemia/lymphoma (T-ALL), an aggressive hematologic tumor affecting children and adolescents. The possibility that Notch could play a significant role in human breast cancer development comes from studies on mouse mammary tumor virus-induced cancer. Numerous findings over the past several years have indicated that alterations in Notch signaling are also responsible for ovarian cancer development. Mention should also be made of the connection between expression of Notch 3 and increased resistance to chemotherapy, which remains a major obstacle to successful treatment. Notch as an oncogenic factor is also involved in the development of colon cancer, lung carcinoma and Kaposi's sarcoma. CONCLUSION: Notch is a binary cell fate determinant and its overexpression has been described as oncogenic in a wide array of human malignancies. This finding led to interest in therapeutically targeting this pathway, especially by the use of gamma-secretase inhibitors (GSIs) blocking the cleavage of Notch receptors at the cell membrane by the inhibition of Notch intracellular domain (NICD) releasing. Preclinical cancer models have revealed that GSIs suppress the growth of cancers such as pancreatic, breast and lung cancer.

Oxidative stress and angiogenesis in primary hyperparathyroidism.

BACKGROUND: The inappropriate elevation of parathormone (PTH), which regulates the process of angiogenesis in parathyroid tissue, causes the changes of activity of enzymes responsible for the removal of free radicals. Parathyroidectomy (PTX) in patients with primary hyperparathyroidism (PHPT) lowers the level of PTH and leads to the reduction of risk of cardiovascular and all-cause mortality by normalization of the antioxidant status. Therefore, the aims of the study were to assess the activity of antioxidant enzymes and free radical reaction products in patients after parathyroidectomy, and to evaluate the correlation between the systemic oxidative stress and angiogenic parameters. MATERIALS AND METHODS: Patients with PHPT treated surgically were enrolled into the study. Total antioxidant capacity (TAC), total oxidative status (TOS), oxidative stress index (OSI), superoxide dismutase (SOD), ceruloplasmin (CER), lipid hydroperoxides (LHP) and malondialdehyde (MDA) were measured before and after parathyroidectomy. The immunohistological expression of angiogenic factors in parathyroid specimens was assessed by the BrightVision method from ImmunoLogic using murine monoclonal anti-human: anti-VEGF, anti-CD31 and anti-CD106 antibodies. RESULTS: The significant increase of TAC, CER, reduction of TOS, MDA, SOD, especially for cytoplasmic form, and significant decrease of OSI, LHP were observed after PTX. There was no significant correlation between changes of oxidative stress markers and angiogenic parameters: VEGF, CD-31, CD-106 in parathyroid tissue. The correlation level was low and medium. CONCLUSIONS: Parathyroidectomy causes down-regulation of lipid peroxidation processes and leads to reduction of oxidative stress in patients with PHPT. The decrease in the OSI is the results of down-regulation of oxidative stress in the postoperative period. The change of the antioxidant status has no impact on angiogenesis processes in parathyroid tissue.

Expression of TRAIL and Fas in Primary Hyperparathyroidism.

AIM: Differentiating between parathyroid lesions is still difficult and ambiguous. In cases of primary hyperparathyroidism, appropriate and prompt diagnosis is of great importance for effective treatment and follow-up. A great amount of mechanisms contribute to the pathogenesis of primary hyperparathyroidism, such as disturbance in balance between pro- and anti-apoptotic factors. Therefore, we examined whether immunohistochemical expression of apoptotic factors, TNF-related apoptosis-inducing ligand (TRAIL) and Fas, could have clinical utility as a marker of proliferative lesions of parathyroid gland. MATERIALS AND METHODS: Parathyroid specimens of 58 consecutive patients who had undertaken surgery due to primary hyperparathyroidism were incubated with purified mouse monoclonal antihuman antibodies: anti-TRAIL and anti-Fas. Staining was considered positive when at least 5% of the cells showed immunoreactivity. RESULTS: The percentage of cells which were positively stained for TRAIL in parathyroid hyperplasia was 9.65%, in parathyroid adenoma 8.31%, and in normal controls 2.24%. Immunoreactivity for TRAIL was detected in 91.89% of parathyroid hyperplasias, 85.71% of parathyroid adenomas, and none in healthy glands. The percentage of cells with a positive reaction to Fas in parathyroid hyperplasia was 8.92%, in parathyroid adenoma 8.09%, and in normal tissue 1.9%. The expression of Fas was found in 94.59% of parathyroid hyperplasias, 90.48% of parathyroid adenomas, and none in healthy glands. CONCLUSIONS: In our study, hyperplasias demonstrated the highest expression of TRAIL and Fas, whereas in adenomas it was increased compared to normal tissue, but lower than in hyperplasias. These factors could be an additive tool in the differential diagnosis of parathyroid lesions.

Immunohistochemical assessment of mitochondrial superoxide dismutase (MnSOD) in colorectal premalignant and malignant lesions.

INTRODUCTION: It is generally accepted that mitochondria are a primary source of intracellular reactive oxygen species (ROS). Under physiological circumstances they are permanently formed as by-products of aerobic metabolism in the mitochondria. To counter the harmful effect of ROS, cells possess an antioxidant defence system to detoxify ROS and avert them from accumulation at high concentrations. Mitochondria-located manganese superoxide dismutase (MnSOD, SOD2) successfully converts superoxide to the less reactive hydrogen peroxide (H2O2). To the best of our knowledge, there are no available data regarding immunohistochemical expression of MnSOD in colorectal neoplastic tissues. AIM: To investigate the immunohistochemical expression status of MnSOD in colorectal premalignant and malignant lesions. MATERIAL AND METHODS: This study was performed on resected specimens obtained from 126 patients who had undergone surgical resection for primary sporadic colorectal cancer, and from 114 patients who had undergone colonoscopy at the Municipal Hospital in Jaworzno (Poland). Paraffin-embedded, 4-µm-thick tissue sections were stained for rabbit polyclonal anti SOD2 antibody obtained from GeneTex (clone TF9-10-H10 from America Diagnostica). RESULTS: Results of our study demonstrated that the development of colorectal cancer is connected with increased expression of MnSOD both in adenoma and adenocarcinoma stages. Samples of adenocarcinoma with G2 and G3 grade showed significantly higher levels of immunohistochemical expression of this antioxidant enzyme. Moreover, patients with the presence of lymphovascular invasion and higher degree of regional lymph node status have been also characterised by higher levels of MnSOD expression. The samples of adenoma have been characterised by higher levels of MnSOD expression in comparison to normal mucosa as well. Interestingly, there was no significant correlation between expression and histological type of adenoma. CONCLUSIONS: Development of colorectal cancer is connected with increased expression of MnSOD both in adenoma and adenocarcinoma stages.

Response to Dual Antiplatelet Therapy Does Not Impact Bleeding Risks in Patients Undergoing Oral Surgery after Acute Coronary Syndromes.

INTRODUCTION: Oral surgery (OS) in patients on antecedent dual antiplatelet therapy (DAPT) may be associated with extra bleeding risks. Monitoring platelet activity in such patients may be beneficial for safety when performing OS. OBJECTIVES: The aim of this study was to assess whether platelet function during DAPT impacted the risk of bleeding following OS in patients with acute coronary syndromes (ACS). PATIENTS AND METHODS: Patients who required OS on top of DAPT with aspirin and clopidogrel (n = 55) for invasively treated ACS were included. The control group (n = 33) consisted of patients who underwent OS with no antiplatelet agent. Platelet aggregation before OS was assessed with a Multiplate® analyzer. Bleeding during OS and at days 1, 3, 7 and 10 after surgery was serially evaluated. RESULTS: All 88 patients completed the study. An incomplete response to aspirin or clopidogrel was observed in 43.6% of the patients. In 11% of the cases, an excessive response to clopidogrel was demonstrated. No excessive bleeding upon OS was exhibited in either group during the entire follow-up. Platelet aggregation values and the use of DAPT did not impact the performance of OS. CONCLUSION: Therapy with clopidogrel and aspirin after ACS does not seem to increase the risk of real-life bleeding following OS, regardless of the platelet activity response to DAPT. © 2015 S. Karger AG, Basel.

Angiogenesis in primary hyperparathyroidism.

Angiogenesis can be described as a formation of new vessels from the existing microvasculature and is a process of great importance to the tumor development. Parathyroid tissue can trigger spontaneous induction of angiogenesis in vitro and in vivo models in a vascular endothelial growth factor (VEGF)-dependent manner. Autotransplantated parathyroid tissue after thyroidectomy is able to form new vasculature and produce parathormone, maintaining calcium homeostasis. A great amount of factors contributes to the process of new vessel formation in primary hyperparathyroidism, such as VEGF, transforming growth factor ß, and angiopoietins. Studies demonstrated that markers for angiogenesis can be useful in distinguishing between parathyroid hyperplasia and neoplasia, due to the increased angiogenesis in parathyroid proliferative lesions compared with parathyroid adenomas. These factors include, inter alia, VEGF, VEGFR2, CD105, and fibroblast growth factor-2. Although these differences appear promising in the differential diagnosis, there is an overlap between benign and malignant parathyroid lesions and there is no definite cutoff value. Loss of heterozygosity and comparative genomic hybridization studies revealed chromosomal regions frequently altered in parathyroid tumorigenesis at 9p21, 1p21-22, 1p35-36, and 11q13. Therefore, immunohistochemistry and genetic testing should be an additional diagnostic marker in combination with the traditional criteria. A better understanding of angiogenesis in primary hyperparathyroidism could result in more precise assessment of diagnosis and more effective treatment, especially in those cases, in which the commonly used parameters are insufficient.

Biomolecular mechanisms in varicose veins development.

Varicose veins (VVs) can be described as tortuous and dilated palpable veins, which are more than 3 mm in diameter. They are one of the clinical presentations of chronic venous disorders, which are a significant cause of morbidity. The prevalence of VVs has been estimated at 25-33% in women and 10-20% in men and is still increasing at an alarming rate. Family history, older age, female, pregnancy, obesity, standing occupations, and a history of deep venous thrombosis are the predominant risk factors. A great amount of factors are implicated in the pathogenesis of VVs, including changes in hydrostatic pressure, valvular incompetence, deep venous obstruction, ineffective function of calf muscle pump, biochemical and structural alterations of the vessel wall, extracellular matrix abnormalities, impaired balance between growth factors or cytokines, genetic alterations, and several other mechanisms. Nevertheless, the issue of pathogenesis in VVs is still not completely known, even if a great progress has been made in understanding their molecular basis. This kind of studies appears promising and should be encouraged, and perhaps the new insight in this matter may result in targeted therapy or possibly prevention.

Molecular profiling in primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (HPT) is one of the most common endocrine disorders, defined by hypersecretion of parathormone. Primary HPT can be caused by adenoma, hyperplasia, and carcinoma. A great amount of mechanisms contribute to the pathogenesis of this disease, such as genetic predispositions because of the germline-inactivating mutations in the multiple endocrine neoplasia type 1 (MEN1) and HRPT2 tumor suppressor genes. Somatic mutations in these genes were found also in sporadic parathyroid neoplasias. Cell cycle regulators, growth factors, apoptosis-inducing ligands, death receptors, and other transmitter substances have also been implicated in the etiology of primary HPT. Parathyroid carcinoma is often misdiagnosed as parathyroid adenoma and long-term survival is conditioned by the extent of the primary surgical resection, therefore, of great interest is the discovery of definitive diagnostic markers for carcinoma. This article presents current state of knowledge of the molecular pathogenesis of primary HPT.

The relationship between late gadolinium enhancement imaging and myocardial biopsy in the evaluation of chronic heart failure patients with suspected myocarditis.

AIM: The aim of this study was to assess the relationship between late gadolinium-enhanced (LGE) cardiovascular magnetic resonance (CMR) and immunohistochemical markers of inflammation in patients with heart failure and a reduced ejection fraction (HFrEF). MATERIAL AND METHODS: Endomyocardial biopsy and CMR were performed in 38 consecutive patients (24 males, average age 43.2 ± 6.9 years, New York Heart Association [NYHA] class II) with HFrEF and suspected myocarditis. The immunohistochemical evaluation was done by the En-Vision system using DAKO monoclonal antibodies. The presence of > 14 infiltrating cells together with myocardial damage and ≥ 2 + up-regulation of HLA class II was considered diagnostic for myocarditis. The results of LGE were compared with the immunohistochemical markers of inflammation. All patients underwent coronary angiography. RESULTS: Twelve out of 38 (31.6%) patients met the immunohistological criteria for the diagnosis of myocarditis. Late gadolinium enhancement was present in 23 of 38 (60.5%) patients, mostly at the interventricular septum. No correlation was found between LGE and immunohistochemistry results (Kendall's tau; r = 0.21, p = 0.09). CONCLUSIONS: Our study revealed no significant relationship between LGE cardiovascular magnetic resonance imaging and immunohistochemical markers of inflammation in patients with HFrEF.