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A 53-year-old female was admitted to the cardiology department on account of signs and symptoms of congestive heart failure (HF) with severe peripheral edema and dyspnea on exertion (New York Heart Association class III) for the past 3 months.

Background: The etiology of keratoconus is unclear. Current evidence suggests that inflammatory and systemic mechanisms might play a role in its pathophysiology. The proper interaction of proteolytic enzymes-matrix metalloproteinases-and their specific tissue inhibitors (TIMPs) within the cornea is essential in maintaining its structure, transparency and healing processes. The aim of the study was to determine the concentration of the TIMPs TIMP-1, TIMP-2, TIMP-3, and TIMP-4 in the blood serum samples of patients with keratoconus compared to the control group., Methods: The study encompassed 132 patients, of which 83 people constituted the study group and 49 the control group. The concentration of selected TIMPs was determined using the Human Magnetic Luminex ® Performance Assay method., Results: In the study group, the concentrations of TIMP-1 and TIMP-3 were statistically significantly reduced, and TIMP-2 and TIMP-4 increased compared to the control group. The analysis of individual TIMPs in terms of their usefulness as potential predictors of keratoconus showed high results of diagnostic sensitivity and specificity for all TIMPs, in particular for TIMP-1 and TIMP-2., Conclusion: The above results may indicate systemic disturbances in the TIMPs regulation among keratoconus patients. High diagnostic sensitivity and specificity of all TIMPs, in particular TIMP-1 and TIMP-2, may confirm their participation in the etiopathogenesis of this disease.

Myocarditis is an inflammatory disease of the myocardium caused by infectious or non-infectious agents. It can lead to serious short-term and long-term sequalae, such as sudden cardiac death or dilated cardiomyopathy. Due to its heterogenous clinical presentation and disease course, challenging diagnosis and limited evidence for prognostic stratification, myocarditis poses a great challenge to clinicians. As it stands, the pathogenesis and etiology of myocarditis is only partially understood. Moreover, the impact of certain clinical features on risk assessment, patient outcomes and treatment options is not entirely clear. Such data, however, are essential in order to personalize patient care and implement novel therapeutic strategies. In this review, we discuss the possible etiologies of myocarditis, outline the key processes governing its pathogenesis and summarize best available evidence regarding patient outcomes and state-of-the-art therapeutic approaches.

Nucleolar dominance (ND) is selective epigenetic silencing of 35-48S rDNA loci. In allopolyploids, it is frequently manifested at the cytogenetic level by the inactivation of nucleolar organiser region(s) (NORs) inherited from one or several evolutionary ancestors. Grasses are ecologically and economically one of the most important land plant groups, which have frequently evolved through hybridisation and polyploidisation events. Here we review common and unique features of ND phenomena in this monocot family from cytogenetic, molecular, and genomic perspectives. We highlight recent advances achieved by using an allotetraploid model grass, Brachypodium hybridum, where ND commonly occurs at a population level, and we cover modern genomic approaches that decipher structural features of core arrays of NORs., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Myocarditis and inflammatory dilated cardiomyopathy are cardiac diseases leading to heart failure. Liquid biopsy is a concept of replacing traditional biopsy with specialized blood tests. The study aim was to summarize and assess the usefulness of microRNAs and circulating free DNA as biomarkers of myocardial inflammation. For this systematic review, we searched Scopus, Embase, Web of Science, and PubMed. All studies measuring microRNAs in serum/plasma/cardiac tissue or circulating free DNA during myocarditis and non-ischemic dilated cardiomyopathy in humans in which healthy subjects or another cardiac disease served as a comparator were included. Data were extracted and miRNAs were screened and assessed using a scale created in-house. Then, highly graded miRNAs were assessed for usability as liquid biopsy biomarkers. Of 1185 records identified, 56 were eligible and 187 miRNAs were found. We did not identify any studies measuring circulating free DNA. In total, 24 of the screened miRNAs were included in the final assessment, 3 of which were selected as the best and 3 as potential candidates. We were not able to assess the risk of bias and the final inclusion decision was made by consensus. Serum levels of three miRNAs-miR-Chr8:96, miR-155, and miR-206-are the best candidates for myocardial inflammation liquid biopsy panel. Further studies are necessary to prove their role, specificity, and sensitivity.

Granulomatosis with polyangiitis (GPA) is a rare systemic vasculitis that classically affects the upper respiratory tract, lungs, and kidneys. The involvement of other organs occurs but is less frequent. Clinically overt cardiac involvement is rare. We present a rare case of thoracic pain caused by cardiac involvement in GPA, without any other symptoms. The diagnosis was made using an integral approach, with several complementary imaging modalities, including cardiac histology.

BACKGROUND Cardiac inflammatory pseudotumors are rarely observed. Their etiology might include immunologic abnormalities, fibrogenetic disorders, specific reactions to infections or abnormalities related to trauma, necrosis, or neoplasm. Life-threatening ventricular tachycardia and cases of sudden death related to cardiac tumors have been reported. The present report describes and discusses diagnostic and therapeutic solutions for the treatment of nonsarcoid multiorgan pseudotumors with cardiac involvement. CASE REPORT A 38-year-old woman presented to the clinic with symptomatic ventricular tachycardia. As coronary artery disease, cardiomyopathy, and channelopathy were ruled out, and electrocardiograms were not typical of idiopathic arrhythmia, the patient underwent detailed diagnostics which included targeted endomyocardial biopsy, which revealed a cardiac inflammatory pseudotumor. Laborious testing (and eventually, antibiotic therapy) led to ex juvantibus diagnosis of multiorgan disseminated brucellosis with cardiac involvement. Treatment with ceftriaxone, doxycycline, and rifampicin resulted in a complete resolution of all lesions after 3 months, and sustained recovery was observed during a 5-year follow-up. As the risk of ventricular tachycardia could not be reliably predicted, the patient had a subcutaneous implantable cardioverter-defibrillator implanted. CONCLUSIONS A vast diagnostic armamentarium of modern medicine allowed us to diagnose an unsuspected and rare cardiac inflammatory pseudotumor. In the case of travelers, the possibility of regionally specific illnesses, especially infections, must be taken into consideration as possible causes of arrhythmias. Cardiac magnetic resonance imaging may be useful in patients with 'idiopathic ventricular tachycardias' to detect non-apparent myocardial lesions which may result from the underlying cause of the arrhythmia.

Background: It is still uncertain whether de-novo expression of E-selectin in endothelial cells may be considered an additional marker of chronic inflammation in heart failure (HF)., Methods: We studied 393 consecutive patients (313 M, 80 F) with HF secondary to dilated cardiomyopathy in whom the right ventricular endomyocardial biopsy was performed. For immunohistochemistry, HLA class I and II, E-selectin (ELAM-1), CD3 + lymphocytes and CD68 + macrophages were studied. Patients were divided into two groups: Group A, with ELAM-1 (+), and Group B with ELAM-1 (-) in the biopsy sections., Results: Of all patients, 140 (35.6%) subjects were presented with ELAM-1 expression in endomyocardial biopsies. Patients in the Group A had a significantly lower LV ejection fraction compared to those from the Group B (31.3 ± 12.9 vs. 34.2 ± 12.7; 95% CI, 0.3-5.6, P = 0.029) and they showed a higher mean number of CD3 (+) lymphocytes in the biopsy sections, P = 0.006. In addition, ELAM-1 reasonably correlated with CD3 lymphocytes (r = 0.3, P < 0.001)., Conclusions: Our findings suggest that de-novo ELAM-1 expression in endothelial cells may be a useful marker of chronic inflammation in the biopsies of patients with HF secondary to dilated cardiomyopathy., (Copyright © 2022. Published by Elsevier GmbH.)

Accumulated evidence suggest that the adverse outcome of severe coronavirus disease 2019 (COVID-19) is closely related to prothrombotic microvascular pathology with a high risk of venous thromboembolism. Furthermore, the first observational studies indicated that adjunct therapy with low-molecular weight heparin (LMWH) was associated with lower mortality in this cohort of patients. However, the timing of starting LMWH and the dose remain controversial in COVID-19 patients. Considering the above, the aim of this study was to reveal the rationale for using LMWH in the therapy of symptomatic COVID-19 patients based on experimental and clinical studies on LMWH in inflammatory settings with special consideration given to randomized trials., Competing Interests: Conflict of interest: Authors state no conflict of interest, (© 2022 Edyta Reichman-Warmusz et al., published by De Gruyter.)

Aims: So far, little has been known on whether myocardial inflammatory infiltration influences heart failure (HF) progression. Thus, the aim of this study was to test the impact of intramyocardial infiltration on clinical outcomes., Methods: Biopsy samples from 358 patients with stable HF secondary to dilated cardiomyopathy were studied. Immunohistochemistry for lymphocyte (CD3) and macrophage (CD68) markers was performed and counted. After a 1-year follow-up, patients were classified as improved based on the predefined definition of improvement. The clinical data were collected from 324 patients (90.5%)., Results: According to the predefined definition of improvement, 133 patients improved (41.0%) but 191 remained unchanged or deteriorated (58.9%). After a 12-month follow-up, the OR with 95% CI of counts of myocardial inflammatory CD68-positive ≥4 cell/high power field (HPF) compared with CD68-positive <4 cell/HPF for lack of improvement was 1.91 (1.65-2.54). However, the number of CD3 positive cell infiltration had no impact on clinical outcome after a 1-year follow-up. In the baseline study, a reasonably negative correlation was found between the number of CD68 positive cells and troponin T (r=-0.39; p<0.001 by Spearman's r). This was corroborated with a low negative correlation between these cells and myocardial form of creatine kinase (CK-MB) fraction (r=-0.27; p=0.006). There was no correlation between CD3 and CD68 positive cells (Spearman's r; r=-0.17, p=0.16)., Conclusions: The current results provide evidence that high macrophage counts may be a predisposing factor for HF progression., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Endothelial dysfunction is a critical part of heart failure (HF) pathophysiology. It is not clear, however, whether it is present at the similar level in the early and late HF stages., Material and Methods: von Willebrand factor (vWF) and its mRNA levels in biopsies of non-ischemic patients with HF secondary to dilated cardiomyopathy were studied. Consecutive patients with HF were divided into two groups: group A with disease duration ≤ 12 months (n = 59) and group B with disease duration > 12 months (n = 68). The immunoreactivity of the vWF was compared with autopsy sections of 19 control cases. Tissue vWF gene expression was analyzed at the mRNA level by RT-PCR., Results: In the group A, there was lower vWF immunoreactivity in the coronary microvessels compared to the group B [1.5 (1.0-2.0) vs. 2.0 (1.5-2.4), P = 0.001]. In the control group, only weak vWF expression was observed. Protein expression was not accompanied by vWF mRNA whose levels were significantly higher in the Group A as compared to the Group B [14671 (4932-51561) vs. 3643 (185.3-9030.8), P = 0.005]. Protein vWF expression was inversely associated with its mRNA levels (r = -0.34, P = 0.04)., Conclusions: High myocardial protein expression of vWF in patients with long-lasting HF symptoms may highlight the persistent nature of endothelial dysfunction in such a cohort of patients.

Introduction: Cardiac papillary fibroelastomas (CPFs) are rare benign cardiac tumors typically found on the heart valves. The previously published data on the CPF focused on its clinical presentation, optimal management, and prognosis. However, histogenesis of these lesions remains controversial. Accordingly, the aim of this study was to establish the role of endocardial endothelium (EE) in CPF formation., Materials and Methods: Four CPF tumors removed from the right atrioventricular valves were analyzed using hematoxylin & eosin, orcein, and Masson trichrome staining together with immunochemistry for CD-34, CD-68, vimentin, vWF and a-SMA. Moreover, conventional transmission electron microscopy was used for morphological analysis and a-SMA presence confirmation., Results: Ultrastructural morphology, immunohisto- and immunocytochemical analyses indicated that cells covering collagenous core have an endothelial origin. Some endocardial endothelium cells have the potential to undergo a transition to mesenchymal cells. Moreover, the abundant presence of extracellular vesicles may indicate an active intercellular communication. Within the intermediate translucent zone, amorphous substances with monocytes/macrophage-like cells and fibroblastic cells were found. Finally, within collagenous core activated (myo)fibroblasts were observed., Conclusions: Our study demonstrated that the endocardial endothelium of the CPF was "double-sided", i.e., it presented both endothelial and mesenchymal cell characteristics. Another finding was the presence of monocytes, and macrophages which were integrated into CPF core and displayed features of a fibroblast that have been shown to contribute to extracellular matrix production. This could be interpreted as being attributed to the CPF histogenesis.

In the summer of 2019, an epidemic of e-cigarette or vaping product use associated lung injury (EVALI) broke out in the United States of America. EVALI is a lung disease that can be severe and life-threatening. It should be emphasized that EVALI is not a clinical diagnosis, but surveillance case definition. Due to the profile of users of such devices, the pathology mainly affects young adults, although cases of EVALI have been reported in almost all age groups, from teenage children to seniors. The worst prognosis is in patients over 35 years of age, with accompanying diseases. A significant number of patients declared the use of products containing tetrahydrocannabinol (THC). The most likely factor responsible for the occurrence of EVALI is vitamin E acetate, which is sometimes added to liquids necessary for the use of electronic cigarette type devices, especially those liquids that contain THC. Nevertheless, it is possible that other substances used in liquids may also be a causative factor. Typical for EVALI are respiratory, gastrointestinal and systemic symptoms, while in imaging tests, a characteristic feature of EVALI is the presence of opacities on the chest radiogram and ground-glass clouds on computed tomography scans. In the course of this disease, respiratory failure often occurs (58%). In the vast majority of cases oxygen substitution is necessary. Currently, the best treatment of EVALI is considered to be the administration of systemic glucocorticosteroids. Over 90% of patients with EVALI required hospitalization, while the mortality rate was about 2.42%. Median age of the fatalities was 51 years. The aim of this review is to summarise the available information on EVALI and to consider possible causative factors and pathomechanism., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

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.

Objective: The aim of this study was to assess the role of potential factors explaining variability of serum uric acid (SUA) levels in patients with chronic heart failure with reduced ejection fraction (HFrEF) not receiving xanthine oxidase inhibitors and acetylsalicylic acid, with multivariate adaptive regression splines and fuzzy c -regression models., Material and Methods: Between 1998 and 2010, we prospectively enrolled 294 patients (44 females, 250 males; mean age 43.1±11.6 years) not receiving allopurinol or febuxostat, who underwent right ventricular endomyocardial biopsy due to unexplained HFrEF (duration of symptoms ≥6 months) with New York Heart Association functional class II and III and decreased left ventricular ejection fraction <40% in radionuclide study. The following factors were analyzed: left ventricular ejection fraction, concentrations of serum creatinine, high-sensitivity C-reactive protein, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), SUA, glucose, total cholesterol, HDL and LDL fractions of cholesterol, triglycerides, fibrate, D-dimers, and medication. Multivariate Adaptive Regression Splines, local polynomial smoothing with Epanechnikov kernel function as well as the Time Domain Constrained Fuzzy c -Regression Models were used., Results: SUA concentration variability was explained by BMI, eGFR values, serum NT-pro BNP levels and the use of thiazide diuretics. The SUA declined with eGFR and increased with BMI values, serum NT-proBNP levels and the use of thiazide diuretics. A weak negative correlation between log 10 (SUA) levels and the LVEF was found (r=-0.130; p <0.05)., Conclusions: Kidney function, nutritional status, the use of thiazide diuretics and the severity of left ventricle dysfunction reflected by serum NT-proBNP levels explain the serum uric acid levels variability in patients with HFrEF., (© 2018 by the Association of Clinical Scientists, Inc.)

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.

Background: Psoriasis is a common autoimmune disease of unknown etiology. Recently, much attention has been paid to evidence that a local hypercoagulable state is an important contributing factor to the development of inflammatory skin diseases. Thus, the aim of this study was to characterize the local hemostasis in the affected skin of patients with psoriasis., Methods: Skin biopsies of psoriatic plaques were obtained from 73 consecutive patients (48M, 25F, average age 45 years) with at least a one year history of the disease. The studied patients had not received any specific systemic treatment for at least 4 weeks before the biopsy was done. As a control, normal skin biopsies were obtained from 16 healthy subjects. For immunohistological study, the En-Vision method (DAKO EnVision Kit ®/Alkaline Phosphatase detection system), and monoclonal antibodies anti-tissue factor (TF), anti-thrombomodulin (TM) and anti-von Willebrand Factor (vWF) were used. All these molecules were assessed semi-quantitatively in the frozen sections., Results: Clinically, the Body Surface Area index ranged between 1-90% and the Psoriasis Area Severity Index score ranged from 1.6 to 47. Immunohistochemistry revealed redistribution of TF antigens from the upper to lower layers of the epidermis as compared to the control. It was collaborated with the number of TF-positive cells in the psoriatic skin sections (78.3%) as compared with the healthy subjects (34.4%; P<0.001). In addition, TF was uniformly and moderately expressed on capillary endothelial cells of the plaque sections in 43 out of 73 patients (58.9%). As far as the thrombomodulin is concerned, TM was clearly down-regulated and localized mainly in the upper layers of the psoriatic epidermis. It was collaborated with the number of TM positive cells in the psoriatic skin sections (38.9%) as compared with the healthy subjects (66.7%; P<0.001). All capillary vessels found in the biopsy sections were positive for TM and vWF staining, with similar expression (≥2+) in both groups. In the current study, no relationship was found between the TF, TM and vWF expression and the PASI and BAS (NS)., Conclusions: A local procoagulable state found in psoriatic plaques suggests a significant role of local tissue hemostasis in pathogenesis of the disease. These findings indicate another potential target for a therapeutic approach in patients with psoriasis, although further research would help elucidate the exact mechanisms., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

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.

Laminopathies, a group of heterogeneous disorders associated with lamin A/C gene (LMNA) mutations, encompass a wide spectrum of clinical phenotypes, which may present as separate disease or as overlapping syndromes. We describe a 35-year-old female in whom a novel sporadic heterozygous mutation c.1001&#95;1003delGCC (p.Ser334del) of the LMNA gene was found. The patient presented with overlapping syndrome of heart failure secondary to dilated cardiomyopathy, limb-girdle dystrophy and partial lipodystrophy. Endomyocardial biopsy revealed strong up-regulation of HLA classes I and II antigens on microvessels and induction of the class I antigens on cardiomyocytes. On muscle biopsy, a wide range of fiber sizes and small clusters of inflammatory infiltrations were found. In the rapid progression of heart failure with arrhythmias or conduction defect, accompanied with muscle atrophy and lipodystrophy, the genetic disease should be taken into consideration. In addition, undefined inflammatory response and fibrosis in the heart or skeletal muscle might further justify screening of the lamin A/C gene., Competing Interests: The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Ethical issues All procedures were in accordance with the standards of the bioethical committee and the Declaration of Helsinki.

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 T‑cell 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.

Aims: Several lines of evidence point to hypercoagulability as an important factor for heart failure (HF) pathogenesis., Methods: We hypothesised that endothelial tissue factor (TF) expression reflects altered tissue haemostasis which is related to the severity of HF. Accordingly, we investigated TF expression in the biopsies of 60 patients with HF and 22 without HF. In addition, we assessed the relationship between endothelial TF expression and clinical markers of HF severity., Results: The control subjects without HF presented absent or weak TF expression in few microvessels, while the endomyocardial biopsies of patients with HF, capillary vessels presented both weak and severe staining patterns by immunohistochemistry usually with regional distribution. This was collaborated by the immune electron microscopic study. The severe microvessel TF antigen expression was found in 11 (18.3%) patients with HF. The endothelial TF expression was inversely associated with left ventricular ejection fraction (r=-0.42, p=0.001) and positively with N-terminal brain natriuretic peptide (r=0.36, p<0.023), markers of HF severity., Conclusions: Regional upregulation of the TF in the capillary endothelial cells suggests local myocardial thrombogenicity. Furthermore, the relationship between endothelial TF and HF severity would be keeping in line with the hypothesis that an altered tissue haemostasis is most profoundly expressed in patients with severe HF. Weak TF expression found in several microvessels of the biopsy specimens patients without HF pathology might be potentially related to a low basal level of activation of the clotting system in normal individuals., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The Epstein-Barr virus (EBV), also known as human herpesvirus 4, is a member of the Herpesviridae virus family. EBV infection can cause infectious mononucleosis (IM) in the lytic phase of EBV's life cycle. Past EBV infection is associated with lymphomas, and may also result in certain allergic and autoimmune diseases. Although potential mechanisms of autoimmune diseases have not been clearly elucidated, both genetic and environmental factors, such as infectious agents, are considered to be responsible for their development. In addition, EBV modifies the host immune response. The worldwide prevalence of autoimmune diseases shows how common this pathogen is. Normally, the virus stays in the body and remains dormant throughout life. However, this is not always the case, and a serious EBV-related illness may develop later in life. This explains the chronic course of autoimmune diseases that is often accompanied by exacerbations of symptoms. Based on the present studies, EBV infection can cause autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), Sjögren's syndrome, and autoimmune hepatitis. The EBV has also been reported in patients with autoimmune thyroid disorders. Although EBV is not the only agent responsible for the development of autoimmune thyroid diseases, it can be considered a contributory factor.

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 (H 2 O 2 ). 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., Competing Interests: The authors declare no conflict of interest.

Notch signalling is an evolutionarily conserved signalling pathway, which plays a significant role in a wide array of cellular processes including proliferation, differentiation, and apoptosis. Nevertheless, it must be noted that Notch is a binary cell fate determinant, and its overexpression has been described as oncogenic in a broad range of human malignancies. This finding led to interest in therapeutically targeting this pathway especially by the use of GSIs, which block the cleavage of Notch at the cell membrane and inhibit release of the transcriptionally active NotchIC subunit. Preclinical cancer models have clearly demonstrated that GSIs suppress the growth of such malignancies as pancreatic, breast, and lung cancer; however, GSI treatment in vivo is associated with side effects, especially those within the gastrointestinal tract. Although intensive studies are associated with the role of γ-secretase in pathological states, it should be pointed out that this complex impacts on proteolytic cleavages of around 55 membrane proteins. Therefore, it is clear that GSIs are highly non-specific and additional drugs must be designed, which will more specifically target components of the Notch signalling.

This study aimed to define relationship between PPARα expression and metabolic-structural characteristics during HF progression in hearts with DCM phenotype. Tissue endomyocardial biopsy samples divided into three groups according to LVEF ((I) 45-50%, n = 10; (II) 30-40%, n = 15; (III) <30%, n = 15; and control (donor hearts, >60%, n = 6)) were investigated. The PPARα mRNA expression in the failing hearts was low in Group (I), high in Group (II), and comparable to that of the control in Group (III). There were analogous changes in the expression of FAT/CD36 and CPT-1 mRNA in contrast to continuous overexpression of GLUT-4 mRNA and significant increase of PDK-4 mRNA in Group (II). In addition, significant structural changes of cardiomyocytes with glycogen accumulation were accompanied by increased expression of PPARα. For the entire study population with HF levels of FAT/CD36 mRNA showed a strong tendency of negative correlation with LVEF. In conclusion, PPARα elevated levels may be a direct cause of adverse remodeling, both metabolic and structural. Thus, there is limited time window for therapy modulating cardiac metabolism and protecting cardiomyocyte structure in failing heart.

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 β, 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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., (© 2014 Wiley Periodicals, Inc.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The "double-faced" effect of nitric oxide (NO) is thought to play an important role in triggering and progression of glaucoma., Material/methods: Iris samples were obtained during iridectomy in 35 patients (mean age of 65.4±5.3 years) with diagnosed primary open-angle glaucoma (POAG). The controls were collected postmortem from 10 donors with a mean age of 62.2±1.9 years. Visual field defects were evaluated by perimetry. The Hodapp-Parrish-Anderson classification was used to divide patients into 3 visual field defect groups. The intraocular pressure was measured 3 times before surgery using applanation tonometry. The phenotype activity of nitric oxide synthase (NOS) isoenzymes (endothelial--eNOS and inducible--iNOS) and expression of nitrotyrosine in iris vasculature was assessed., Results: Significant differences were found between glaucoma patients and the controls in eNOS and iNOS activity (Mann-Whitney test, U=35.5, Z=-2.037, p=0.04 and U=21, Z=2.69, p=0.007, respectively). In addition, the results showed an upregulation of nitrotyrosine in the capillary endothelial cells in the study group, which was associated with the duration of diagnosed glaucoma (R-Spearman of 0.33, p=0.0047) and visual field mean defect MD (R-Spearman of 0.29, p=0.019). Moreover, the activity of nitrotyrosine was significantly correlated with iNOS immunoreactivity (R-Spearman of 0.5, p=0.0001). However, the iNOS activity significantly varied among Hodapp-Parrish-Anderson groups (p=0.03)., Conclusions: Our observations confirmed the association between glaucomatous disturbances and upregulation of iNOS, together with increased nitrotyrosine storage.

Snail1 is a zinc-finger transcription factor, which plays a role in colorectal cancer development by silencing E-cadherin expression and inducing epithelialmesenchymal transition (EMT). During EMT tumour cells acquire a mesenchymal phenotype that is responsible for their invasive activities. Consequently, Snail1 expression in colorectal cancer is usually associated with progression and metastasis. Some studies revealed that about 77% of colon cancer samples display Snail1 immunoreactivity both in activated fibroblasts and in carcinoma cells that have undergone EMT. Therefore, expression of this factor in the stroma may indicate how many cells possess the abilities to escape from the primary tumour mass, invade the basal lamina and colonise distant target organs. Blocking snail proteins activity has the potential to avert cancer cell metastasis by interfering with such cellular processes as remodelling of the actin cytoskeleton, migration and invasion, which are clearly associated with the aggressive phenotype of the disease. Moreover, the link between factors from the snail family and cancer stem cells suggests that inhibitory agents may also prove their potency as inhibitors of cancer recurrence.

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.

Background: The impact of myocardial viral persistence on the clinical outcome of patients with dilated cardiomyopathy (DCM) is still open to question., Methods: Fifty-two patients with DCM were enrolled and followed for a median of 3.8 years with respect to death or heart transplantation. Studied patients were clinically stable for at least 6 months before hospitalization. They underwent coronary angiography and endomyocardial biopsy. Specimens were examined by histo- and immunohistochemistry, and the viral genomes of parvovirus B19, cytomegalovirus (CMV), Coxsackie B virus (CVB), and hepatitis B and C viruses were studied by real-time polymerase chain reaction., Results: Forty-two out of 52 patients were available for clinical follow-up. The viral genome was detected in the myocardium of 32 out of 42 patients. Among the viruses studied, CMV and CVB were the most frequently found. Nine out of 42 patients achieved the predefined study end point. No statistically significant correlation was found between the presence of a persistent viral genome and study end point. No statistically significant relationship between viral genomes studied and immunohistology results was detected., Conclusions: High prevalence of a viral genome in the myocardium of patients with DCM did not have an influence on their long-term clinical outcome., (© 2016 S. Karger AG, Basel.)

Vimentin is an intermediate filament protein normally expressed in cells of mesenchymal origin, e.g. myofibroblasts, chondrocytes, macrophages, and endothelial cells. The expression of vimentin, which has been thought of as the main mesenchymal marker, is also detected in tumour tissue. In tumours of the gastrointestinal tract vimentin expression is usually correlated with advanced stage of tumour, lymph node metastasis, and patient survival.

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.

Background: Previous reports have indicated the role of endothelium disturbances, as expressed by von Willebrand factor (vWF) release, in pathophysiology of glaucoma. The objective of this study was to investigate the vWF expression in iris vasculature of patients with primary open-angle glaucoma (POAG)., Material and Methods: Immunohistochemistry of vWF expression was performed on cryostat sections of samples collected at the time of peripheral iridectomy and controls collected from dead donors., Results: Twenty-seven Caucasians age 66.6±3.7 with 5.8±3.7-year history of treated PAOG and 10 controls age 62.2±1.92 with no history of glaucoma. The percentage of patients who presented normal and up-regulation of vWF phenotype expression differed statistically between examined and control groups: 48% versus 100% (p=0.035, chi-square test with Yates' correction). Sex, age, glaucoma duration, and visual field quantitative indices had no impact on vWF expression. A significant correlation between mean pre-surgery intraocular pressure and vWF expression was found (Spearman r=0.42, p=0.03)., Conclusions: Considering the results, it may be suggested that vWF is actively involved in the pathophysiology of glaucoma.

Introduction: Despite advances in medicine, chronic heart failure (CHF) still remains a significant clinical problem associated with poor outcome., Aim of the Study: To determine risk factors for major adverse cardiac events (MACE) in three-year follow-up in patients with CHF of nonischemic etiology., Material and Methods: The prospective study included consecutive hospitalized patients with stable CHF (LVEDD > 57 mm; LVEF < 40%) and symptom duration > 6 months. Study exclusion criteria were: serious neurological and/or psychiatric diseases, stenoses in epicardial coronary arteries in coronarography, active myocarditis confirmed by myocardial biopsy, diseases of the respiratory system with pulmonary hypertension, presence of heart defects, neoplastic or connective tissue disease, documented infectious diseases at least three months before inclusion in the study, diabetes, liver cirrhosis, chronic kidney disease (eGFR < 30 ml/min/1.73 m(2)), alcoholism, planned heart transplantation. Depression severity was assessed with the Beck and the Hamilton Scales. Depression was diagnosed based on the ICD-10 criteria. Clinical follow-up began on admission and lasted three years., Results: The analysis encompassed 199 patients aged 49 (41-54), who met the inclusion/exclusion criteria. Depression was diagnosed in 30% of the patients. Independent factors increasing the risk of MACE (death, transplantation, ventricular assist device, hospitalization) were: depression (HR: 2.26; p < 0.001), E/A index (HR: 1.31; p < 0.01), right ventricular dimension (HR: 1.06; p < 0.01), hsCRP level (HR: 1.06; p < 0.01) and alkaline phosphatase activity in blood serum (HR: 1.01; p < 0.05)., Conclusions: Factors affecting 3-year outcome are: depression, right ventricular dimension, the E/A index, alkaline phosphatase activity and the level of high-sensitivity C-reactive protein (hs-CRP).

Background: The aim of the study was to assess the relationships among serum neopterin (NPT), β2-microglobulin (β2-M) levels, clinical status, and endomyocardial biopsy results of dilated cardiomyopathy patients (DCM)., Methods: Serum NPT and β-2 M were determined in 172 nonischaemic DCM patients who underwent right ventricular endomyocardial biopsy and 30 healthy subjects (ELISA test). The cryostat biopsy specimens were assessed using histology, immunohistology, and immunochemistry methods (HLA ABC, HLA DR expression, CD3 + lymphocytes, and macrophages counts)., Results: The strong increase of HLA ABC or HLA DR expression was detected in 27.2% patients-group A-being low in 72.8% patients-group B. Neopterin level was increased in patients in group A compared to healthy controls 8.11 (4.50-12.57) versus 4.99 (2.66-8.28) nmol/L (P < 0.05). β-2 microglobulin level was higher in DCM groups A (2.60 (1.71-3.58)) and B (2.52 (1.51-3.72)) than in the control group 1.75 (1.28-1.96) mg/L, P < 0.001. Neopterin correlated positively with the number of macrophages in biopsy specimens (P < 0.05) acute phase proteins: C-reactive proteins (P < 0.05); fibrinogen (P < 0.01); and NYHA functional class (P < 0.05) and negatively with left ventricular ejection fraction (P < 0.05)., Conclusions: Neopterin but not β-2 microglobulin concentration reflected immune response in biopsy specimens. Neopterin correlated with acute phase proteins and stage of heart failure and may indicate a general immune and inflammatory activation in heart failure.

Over the years Transmission Electron Microscopy (TEM) has evolved into a powerful technique for the structural analysis of cells and tissues at various levels of resolution. However, optimal sample preservation is required to achieve results consistent with reality. During the last few decades, conventional preparation methods have provided most of the knowledge about the ultrastructure of organelles, cells and tissues. Nevertheless, some artefacts can be introduced at all stagesofstandard electron microscopy preparation technique. Instead, rapid freezing techniques preserve biological specimens as close as possible to the native state. Our review focuses on different cryo-preparation approaches, starting from vitrification methods dependent on sample size. Afterwards, we discuss Cryo-Electron Microscopy Of VItreous Sections (CEMOVIS) and the main difficulties associated with this technique. Cryo-Focused Ion Beam (cryo-FIB) is described as a potential alternative for CEMOVIS. Another post-processing route for vitrified samples is freeze substitution and embedding in resin for structural analysis or immunolocalization analysis. Cryo-sectioning according to Tokuyasu is a technique dedicated to high efficiency immunogold labelling. Finally, we introduce hybrid techniques, which combine advantages of primary techniques originally dedicated to different approaches. Hybrid approaches permit to perform the study of difficult-to-fix samples and antigens or help optimize the sample preparation protocol for the integrated Laser and Electron Microscopy (iLEM) technique.

Gastric cancer is one of the most common cancers in the world. More than 95% of gastric cancers are adenocarcinomas originating from the glandular epithelium of the stomach lining. Unfortunately, a large number of patients are diagnosed when the tumour is at unresectable stage. Therefore, it is very important to understand the mechanisms involved in gastric cancer pathogenesis. One of them is angiogenesis, which means the formation of new blood vessels from pre-existing vasculature. This process is dependent on interactions between the tumour and surrounding stromal cells which create the tumour microenvironment. Moreover, both tumour and stromal cells release a wide array of angiogenic factors that have an influence on endothelial cell recruitment and thus affect the process of angiogenesis. In this paper we discuss the role of tumour microenvironment in gastric cancer angiogenesis.

Angiogenesis is a complex multistep process by which new capillary structures arise from pre-existing vessels in response to angiogenic stimuli. This process plays a key role during tumorigenesis because the vascular network within the tumor enables malignant cells to establish distant metastases. Thus, it is not surprising that targeting tumors with angiogenesis-based therapy remains a significant area of preclinical and clinical studies. One of the most prominent factors considered as a promising target in such therapy is the Notch ligand Delta-like 4 (DLL4). Emerging evidence suggests that blockade of DLL4 in tumors results in excessive but non-productive angiogenesis which affects tumor growth, even in tumors which are insensitive to anti-VEGF therapy. Nevertheless, the careful evaluation of adverse effects on normal organs' physiology in relation to therapeutic doses of DLL4 inhibitors will be critical for advancement of DLL4 blocking agents in clinical practice.

Notch signaling pathway is activated dynamically during evolution playing significant role in cell fate determination and differentiation. It has been known that alterations of this pathway may lead to human malignancies, including gastric cancer. Despite a decline in the overall incidence, this disease still remains an important global health problem. Therefore, a better understanding of the molecular alterations underlying gastric cancer may contribute to the development of rationally designed molecular targeted therapies. It has been reported that Notch1 receptor could become a prognostic marker of gastric cancer and novel target for gastric cancer therapy. Among the novel and targeted approaches for the treatment of gastric cancer is also the process of Notch receptors regulation by specific microRNA. γ-secretase inhibitors are also taken into consideration.