Recurrent Infective Endocarditis of the Mitral Valve after Orthotopic Heart Transplantation.

Introduction: Orthotopic heart transplantation is the gold standard for the treatment of advanced heart failure in the absence of contraindications. Infective endocarditis is a rare complication in patients after heart transplantation. The treatment of endocarditis after heart transplantation is challenging since there is a need for ongoing immunosuppression. Case description: We present the case of a 51-year-old orthotopic heart transplant recipient enrolled in a chronic dialysis program, in whom we diagnosed and successfully treated recurrent infective endocarditis of the mitral valve caused by Enterococcus and Enterobacter species. Despite the complicated course of the disease, the treatment was successful. Conclusions: Recurrent infective endocarditis after heart transplantation can be treated successfully with a multidisciplinary approach and robust antimicrobial therapy. LEARNING POINTS: There is a high risk of bacteraemia and subsequent endocarditis in patients with recurrent catheter-related sepsis.The spectrum of bacteria causing endocarditis in patients after heart transplantation differs from that in the general population.Scrupulous targeted antibiotic treatment is warranted for the treatment of immunosuppressed patients with endocarditis.

Obesity as a risk factor in atrial fibrillation and heart failure.

Objectives: The aim of this article is to provide an insight into the role of obesity as a risk factor, and as a potential etiologic agent of atrial fibrillation (AF) and heart failure (HF). Methods: A narrative (non-systematic) review article summarizing currently available data regarding the interaction between obesity, AF and HF. Results: Obesity is considered a risk factor of AF and chronic HF. Multiple recent studies indicate that obesity is also a potential causal factor in the development of AF and HF, the elucidation of pathological mechanisms of which could help devise new diagnostic and therapeutic modalities for these conditions. The discussion about obesity in relation to HF cannot omit the so-called obesity paradox, which represents a dilemma for clinicians, and it is still a source of irregularities regarding the strategy of weight reduction in obese patients with HF. Recently, the obesity paradox has also been assumed to play a role in the relationship between obesity and thromboembolic complications of AF. Conclusions: Obesity is an independent and modifiable risk factor for AF and HF. In addition, there is an increasing volume of experimental and clinical data that suggests an important role of the epicardial adipose tissue in the pathophysiology of AF. However, several issues, such as the issue of optimal pharmacotherapy and weight reduction strategy in obese patients with HF remains still unanswered, and open for future investigation.

A Fast-Growing Myxoma of the Left Atrium.

Introduction: Myxoma of the left atrium is a less typical cause of mitral obstruction. If this develops, a flash pulmonary oedema can be the first manifestation. Case description: We present a case report of a 50-year-old woman who was admitted to our internal department because of dyspnoea. The patient overcame a stroke three years before the index hospitalisation with a negative transthoracic echocardiography. By anamnesis and physical examination, an exacerbation of COPD was assumed, and the patient was treated accordingly. As the patient showed numerous risk factors for heart failure with preserved ejection fraction, transthoracic echocardiography was performed. A large polypoid mass was found in the left atrium, which caused severe mitral obstruction. Subsequent transoesophageal echocardiography confirmed this finding. The patient underwent urgent cardiac surgery, and the tumour was successfully resected. A histological examination revealed a cardiac myxoma. After the cardiac surgery the patient felt well, and no recurrence of the tumour occurred. Conclusions: We provide a case report of a fast-growing myxoma that was incidentally found in a patient with dyspnoea. We highlight the fast growth rate of the tumour and the potential for misdiagnosed signs of pulmonary oedema caused by mitral obstruction. LEARNING POINTS: Myxomas are the most common primary tumours of the heart, which can manifest a variety of symptoms such as fever, weight loss, thromboembolism, or mitral obstruction.The symptoms of acute exacerbation of COPD and cardiogenic pulmonary oedema can overlap and can be difficult to differentiate by anamnesis and physical examination alone.Transthoracic echocardiography has a high sensitivity for cardiac masses and is the examination of choice when these are suspected.

A Rare Early-Onset Fatal Complication after Transarterial Chemoembolization: A Case Report and Review of the Literature.

Transarterial chemoembolization (TACE) is a minimally invasive treatment for liver cancer, often employed as a bridging therapy or destination treatment for non-operable cases. This case report discusses an 82-year-old woman with a large hepatocellular carcinoma (HCC) who underwent elective TACE due to the high surgical risk associated with her tumor size. Unexpectedly, the patient experienced liver rupture 20 h post-procedure, leading to acute surgical intervention. Despite successful hemostasis during surgery, the patient succumbed to progressive multi-organ failure. We aimed to search the PubMed database for documented cases of ruptured HCC after TACE. This study highlights risk factors for spontaneous HCC rupture and specific factors associated with TACE-induced rupture. Transarterial embolization (TAE) is currently favored as the treatment method for spontaneous ruptures, while the optimal therapy for TACE-induced ruptures remains unclear. In conclusion, this case underscores the importance of recognizing the rare complication of HCC rupture post-TACE and the need for personalized risk assessment. While TAE emerges as a primary treatment choice, the lack of consensus necessitates further studies to establish evidence-based approaches for managing this uncommon yet life-threatening complication.

Application of Liquid Chromatography Coupled to Mass Spectrometry for Direct Estimation of the Total Levels of Adenosine and Its Catabolites in Human Blood.

Adenosine is a multifunctional nucleoside with several roles across various levels in organisms. Beyond its intracellular involvement in cellular metabolism, extracellular adenosine potently influences both physiological and pathological processes. In relation to its blood level, adenosine impacts the cardiovascular system, such as heart beat rate and vasodilation. To exploit the adenosine levels in the blood, we employed the liquid chromatography method coupled with mass spectrometry (LC-MS). Immediately after collection, a blood sample mixed with acetonitrile solution that is either enriched with 13C-labeled adenosine or a newly generated mixture is transferred into the tubes containing the defined amount of 13C-labeled adenosine. The 13C-enriched isotopic adenosine is used as an internal standard, allowing for more accurate quantification of adenosine. This novel protocol for LC-MS-based estimation of adenosine delivers a rapid, highly sensitive, and reproducible means for quantitative estimation of total adenosine in blood. The method also allows for quantification of a few catabolites of adenosine, i.e., inosine, hypoxanthine, and xanthine. Our current setup did not allow for the detection or quantifying of uric acid, which is the final product of adenosine catabolism. This advancement provides an analytical tool that has the potential to enhance our understanding of adenosine's systemic impact and pave the way for further investigations into its intricate regulatory mechanisms.

Unilateral upper and lower limb ischemia mimics stroke: a case report.

BACKGROUND: Although stroke and acute limb ischemia seem easily distinguishable by anamnesis and physical examination, symptoms may overlap and sometimes mislead the examiner. Such a situation can arise in the occurrence of unilateral neurological symptoms affecting the upper and lower limbs at the same time. As timely diagnosis and a correct therapeutic intervention are crucial to prevent irreversible damage in both diseases, knowledge of the possibility of one disease mimicking the other is essential. We present a unique case of acute unilateral upper and lower limb ischemia mimicking an acute stroke. CASE PRESENTATION: A 69-year-old Caucasian patient with known atherosclerotic risk factors was admitted to the emergency department with a suspected stroke with unilateral paresthesia. After a comprehensive examination of the patient with the need for repeated reevaluation and a negative brain computed tomography scan, acute left-sided upper and lower limb ischemia was eventually diagnosed. The patient underwent surgical revascularization of the upper and lower limbs with a satisfactory result and was discharged from the hospital after a few days. CONCLUSION: It is of utmost importance to always stay alert for stroke mimics, as overlooking can lead to severe complications and delay adequate therapy. Our case shows that persistent diagnostic effort leads to successful treatment of the patient even on rare occasions, as is the acute unilateral upper and lower limb ischemia.

Gastrointestinal Complications of Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS) Syndrome Managed By Parenteral Nutrition.

MELAS - an acronym for mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes - is a multiorgan disease caused by a mutation in mitochondrial DNA (mtDNA). Its clinical manifestations are highly variable; mainly stroke-like episodes, seizures, recurrent headaches, or muscle weakness. However, gastrointestinal complications such as chronic intestinal pseudo-obstruction (IPO), pancreatitis, gastroparesis and hepatopathy are also common. In this report we describe a young patient with gastrointestinal complication of MELAS which led to superior mesenteric artery syndrome (SMAS). It is rare but not surprising combination and should be considered in cases with significant weight loss and resistance to symptomatic treatment. The optimal energy support is the main pillar of the treatment. LEARNING POINTS: Gastrointestinal complications of MELAS such as chronic intestinal pseudo-obstruction, pancreatitis and gastroparesis can lead to undernutrition.Superior mesenteric artery syndrome is a rare condition but should be considered in cases with significant weight loss and resistance to symptomatic treatment.Optimal caloric intake and energy support can improve the condition of patients with MELAS.

Significance of flavonoids targeting PI3K/Akt/HIF-1α signaling pathway in therapy-resistant cancer cells - A potential contribution to the predictive, preventive, and personalized medicine.

BACKGROUND: Cancer management faces multiple obstacles, including resistance to current therapeutic approaches. In the face of challenging microenvironments, cancer cells adapt metabolically to maintain their supply of energy and precursor molecules for biosynthesis and thus sustain rapid proliferation and tumor growth. Among the various metabolic adaptations observed in cancer cells, the altered glucose metabolism is the most widely studied. The aberrant glycolytic modification in cancer cells has been associated with rapid cell division, tumor growth, cancer progression, and drug resistance. The higher rates of glycolysis in cancer cells, as a hallmark of cancer progression, is modulated by the transcription factor hypoxia inducible factor 1 alpha (HIF-1α), a downstream target of the PI3K/Akt signaling, the most deregulated pathway in cancer. AIM OF REVIEW: We provide a detailed overview of current, primarily experimental, evidence on the potential effectiveness of flavonoids to combat aberrant glycolysis-induced resistance of cancer cells to conventional and targeted therapies. The manuscript focuses primarily on flavonoids reducing cancer resistance via affecting PI3K/Akt, HIF-1α (as the transcription factor critical for glucose metabolism of cancer cells that is regulated by PI3K/Akt pathway), and key glycolytic mediators downstream of PI3K/Akt/HIF-1α signaling (glucose transporters and key glycolytic enzymes). KEY SCIENTIFIC CONCEPTS OF REVIEW: The working hypothesis of the manuscript proposes HIF-1α - the transcription factor critical for glucose metabolism of cancer cells regulated by PI3K/Akt pathway as an attractive target for application of flavonoids to mitigate cancer resistance. Phytochemicals represent a source of promising substances for cancer management applicable to primary, secondary, and tertiary care. However, accurate patient stratification and individualized patient profiling represent crucial steps in the paradigm shift from reactive to predictive, preventive, and personalized medicine (PPPM / 3PM). The article is focused on targeting molecular patterns by natural substances and provides evidence-based recommendations for the 3PM relevant implementation.

Role of Platelets in Rheumatic Chronic Autoimmune Inflammatory Diseases.

Platelets are essential in maintaining blood homeostasis and regulating several inflammatory processes. They constantly interact with immune cells, have immunoregulatory functions, and can affect, through immunologically active substances, endothelium, leukocytes, and other immune response components. In reverse, inflammatory and immune processes can activate platelets, which might be significant in autoimmune disease progression and arising complications. Thus, considering this interplay, targeting platelet activity may represent a new approach to treatment of autoimmune diseases. This review aims to highlight the role of platelets in the pathogenic mechanisms of the most frequent chronic autoimmune inflammatory diseases to identify gaps in current knowledge and to provide potential new targets for medical interventions.

The Anti-Thrombotic Effects of PCSK9 Inhibitors.

Atherosclerosis is the primary process that underlies cardiovascular disease. The connection between LDL cholesterol and the formation of atherosclerotic plaques is established by solid evidence. PCSK9 inhibitors have proven to be a valuable and practical resource for lowering the LDL cholesterol of many patients in recent years. Their inhibitory effect on atherosclerosis progression seems to be driven not just by lipid metabolism modification but also by LDL-independent mechanisms. We review the effect of PCSK9 inhibitors on various mechanisms involving platelet activation, inflammation, endothelial dysfunction, and the resultant clot formation. The main effectors of PCSK9 activation of platelets are CD36 receptors, lipoprotein(a), oxidised LDL particles, tissue factor, and factor VIII. Many more molecules are under investigation, and this area of research is growing rapidly.

Modelling Duchenne muscular dystrophy in vitro with newly generated, blood cell-derived induced pluripotent stem cell line ORIONi003-A.

Here, we present newly derived in vitro model for modeling Duchenne muscular dystrophy. Our new cell line was derived by reprogramming of peripheral blood mononuclear cells (isolated from blood from pediatric patient) with Sendai virus encoding Yamanaka factors. Derived iPS cells are capable to differentiate in vitro into three germ layers as verified by immunocytochemistry. When differentiated in special medium, our iPSc formed spontaneously beating cardiomyocytes. As cardiomyopathy is the main clinical complication in patients with Duchenne muscular dystrophy, the cell line bearing the dystrophin gene mutation might be of interest to the research community.

MiR-126 and miR-146a as markers of type 2 diabetes mellitus: a pilot study.

INTRODUCTION: Despite known risk factors for developing type 2 diabetes mellitus (T2D), the research community still tries to discover new markers that would widen our diagnostic and therapeutic approach to diabetes. Therefore, research on microRNA (miR) in diabetes thrives. This study aimed to assess the utility of miR-126, miR-146a, and miR-375 as novel diagnostic markers for T2D. METHODS: We examined relative quantities of miR-126, miR-146a, and miR-375 in the serum of patients with established type 2 diabetes mellitus (n = 68) and compared these with a control group (n = 29). We also undertook a ROC analysis of significantly changed miR to examine their use as a diagnostic test. RESULTS: MiR-126 (p < 0.0001) and miR-146a (p = 0.0005) showed a statistically significant reduction in patients with type 2 diabetes mellitus. MiR-126 also proved to be an exceptional diagnostic test in our study cohort, with high sensitivity (91 %) and specificity (97 %). We did not find any difference in our study groups' relative quantities of miR-375. CONCLUSION: The study proved a statistically significant reduction of miR-126 and miR-146a in patients with T2D (Tab. 4, Fig. 6, Ref. 51). Text in PDF www.elis.sk Keywords: microRNA, epigenetics, genomics, type 2 diabetes mellitus, miR-126, miR-146a and miR-375.

Phytochemical-based nanodrugs going beyond the state-of-the-art in cancer management-Targeting cancer stem cells in the framework of predictive, preventive, personalized medicine.

Cancer causes many deaths worldwide each year, especially due to tumor heterogeneity leading to disease progression and treatment failure. Targeted treatment of heterogeneous population of cells - cancer stem cells is still an issue in protecting affected individuals against associated multidrug resistance and disease progression. Nanotherapeutic agents have the potential to go beyond state-of-the-art approaches in overall cancer management. Specially assembled nanoparticles act as carriers for targeted drug delivery. Several nanodrugs have already been approved by the US Food and Drug Administration (FDA) for treating different cancer types. Phytochemicals isolated from plants demonstrate considerable potential for nanomedical applications in oncology thanks to their antioxidant, anti-inflammatory, anti-proliferative, and other health benefits. Phytochemical-based NPs can enhance anticancer therapeutic effects, improve cellular uptake of therapeutic agents, and mitigate the side effects of toxic anticancer treatments. Per evidence, phytochemical-based NPs can specifically target CSCs decreasing risks of tumor relapse and metastatic disease manifestation. Therefore, this review focuses on current outlook of phytochemical-based NPs and their potential targeting CSCs in cancer research studies and their consideration in the framework of predictive, preventive, and personalized medicine (3PM).

Flavonoids attenuate cancer metabolism by modulating Lipid metabolism, amino acids, ketone bodies and redox state mediated by Nrf2.

Metabolic reprogramming of cancer cells is a common hallmark of malignant transformation. The preference for aerobic glycolysis over oxidative phosphorylation in tumors is a well-studied phenomenon known as the Warburg effect. Importantly, metabolic transformation of cancer cells also involves alterations in signaling cascades contributing to lipid metabolism, amino acid flux and synthesis, and utilization of ketone bodies. Also, redox regulation interacts with metabolic reprogramming during malignant transformation. Flavonoids, widely distributed phytochemicals in plants, exert various beneficial effects on human health through modulating molecular cascades altered in the pathological cancer phenotype. Recent evidence has identified numerous flavonoids as modulators of critical components of cancer metabolism and associated pathways interacting with metabolic cascades such as redox balance. Flavonoids affect lipid metabolism by regulating fatty acid synthase, redox balance by modulating nuclear factor-erythroid factor 2-related factor 2 (Nrf2) activity, or amino acid flux and synthesis by phosphoglycerate mutase 1. Here, we discuss recent preclinical evidence evaluating the impact of flavonoids on cancer metabolism, focusing on lipid and amino acid metabolic cascades, redox balance, and ketone bodies.

COVID-19 and the Response to Antiplatelet Therapy.

The coronavirus SARS-CoV2 disease (COVID-19) is connected with significant morbidity and mortality (3.4%), disorders in hemostasis, including coagulopathy, activation of platelets, vascular injury, and changes in fibrinolysis, which may be responsible for an increased risk of thromboembolism. Many studies demonstrated relatively high rates of venous and arterial thrombosis related to COVID-19. The incidence of arterial thrombosis in severe/critically ill intensive care unit-admitted COVID-19 patients appears to be around 1%. There are several ways for the activation of platelets and coagulation that may lead to the formation of thrombi, so it is challenging to make a decision about optimal antithrombotic strategy in patients with COVID-19. This article reviews the current knowledge about the role of antiplatelet therapy in patients with COVID-19.

Resistance on the Latest Oral and Intravenous P2Y12 ADP Receptor Blockers in Patients with Acute Coronary Syndromes: Fact or Myth?

Novel P2Y12 ADP receptor blockers (ADPRB) should be preferred in dual-antiplatelet therapy in patients with acute coronary syndrome. Nevertheless, there are still patients who do not respond optimally to novel ADP receptor blocker therapy, and this nonoptimal response (so-called "high on-treatment platelet reactivity" or "resistance") could be connected with increased risk of adverse ischemic events, such as myocardial re-infarction, target lesion failure and stent thrombosis. In addition, several risk factors have been proposed as factors associated with the phenomenon of inadequate response on novel ADPRB. These include obesity, multivessel coronary artery disease, high pre-treatment platelet reactivity and impaired metabolic status for prasugrel, as well as elderly, concomitant therapy with beta-blockers, morphine and platelet count for ticagrelor. There is no literature report describing nonoptimal therapeutic response on cangrelor, and cangrelor therapy seems to be a possible approach for overcoming HTPR on prasugrel and ticagrelor. However, the optimal therapeutic management of "resistance" on novel ADPRB is not clear and this issue requires further research. This narrative review article discusses the phenomenon of high on-treatment platelet reactivity on novel ADPRB, its importance in clinical practice and approaches for its therapeutic overcoming.

Tailored Direct Oral Anticoagulation in Patients with Atrial Fibrillation: The Future of Oral Anticoagulation?

Direct oral anticoagulants (DOAC) are currently the drug of choice for drug prevention of stroke or systemic embolism in patients with atrial fibrillation (AF). However, repeated ischemic stroke or systemic embolism and bleeding while on DOAC is still a challenging clinical phenomenon in the management of future long-term anticoagulation. It is not known whether tailoring the DOAC therapy to achieve optimal therapeutic drug levels could improve the clinical course of DOAC therapy. To be able to tailor the therapy, it is necessary to have a valid laboratory method for DOAC level assessment, to be aware of factors influencing DOAC levels and to have clinical options to tailor the treatment. Furthermore, the data regarding clinical efficacy/safety of tailored DOAC regimes are still lacking. This article reviews the current data on tailored direct oral anticoagulation in patients with AF.

SARS-CoV-2 Infection-Associated Aortic Thrombosis Treated with Oral Factor Xa Inhibition.

Coronavirus disease 2019 (COVID-19) is an acute complex systemic disorder caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).While SARS-CoV-2 is known to cause significant pulmonary disease, various extrapulmonary manifestations of COVID-19 have also been reported. Growing evidence suggests that COVID-19 is associated with coagulopathy leading to micro and macrovascular complications. Although in patients with COVID-19, venous thromboembolic events are more frequent, arterial thrombosis also occurs at an increased rate. These often lead to acute life-threatening ischemia, which requires urgent diagnosis and treatment. We present case reports of two patients with an abnormal thrombus formation in the thoracic aorta who recently overcame COVID-19, which led to systemic embolism and splenic infarction. Ambulatory oral factor Xa inhibitor therapy led to aortic thrombosis resolution in both patients.

Antithrombotic and antiplatelet effects of plant-derived compounds: a great utility potential for primary, secondary, and tertiary care in the framework of 3P medicine.

Thromboembolism is the third leading vascular disease, with a high annual incidence of 1 to 2 cases per 1000 individuals within the general population. The broader term venous thromboembolism generally refers to deep vein thrombosis, pulmonary embolism, and/or a combination of both. Therefore, thromboembolism can affect both - the central and peripheral veins. Arterial thromboembolism causes systemic ischemia by disturbing blood flow and oxygen supply to organs, tissues, and cells causing, therefore, apoptosis and/or necrosis in the affected tissues. Currently applied antithrombotic drugs used, e.g. to protect affected individuals against ischemic stroke, demonstrate significant limitations. For example, platelet inhibitors possess only moderate efficacy. On the other hand, thrombolytics and anticoagulants significantly increase hemorrhage. Contextually, new approaches are extensively under consideration to develop next-generation antithrombotics with improved efficacy and more personalized and targeted application. To this end, phytochemicals show potent antithrombotic efficacy demonstrated in numerous in vitro, ex vivo, and in vivo models as well as in clinical evaluations conducted on healthy individuals and persons at high risk of thrombotic events, such as pregnant women (primary care), cancer, and COVID-19-affected patients (secondary and tertiary care). Here, we hypothesized that specific antithrombotic and antiplatelet effects of plant-derived compounds might be of great clinical utility in primary, secondary, and tertiary care. To increase the efficacy, precise patient stratification based on predictive diagnostics is essential for targeted protection and treatments tailored to the person in the framework of 3P medicine. Contextually, this paper aims at critical review toward the involvement of specific classes of phytochemicals in antiplatelet and anticoagulation adapted to clinical needs. The paper exemplifies selected plant-derived drugs, plant extracts, and whole plant foods/herbs demonstrating their specific antithrombotic, antiplatelet, and fibrinolytic activities relevant for primary, secondary, and tertiary care. One of the examples considered is antithrombotic and antiplatelet protection specifically relevant for COVID-19-affected patient groups.

Flavonoids exert potential in the management of hypertensive disorders in pregnancy.

Hypertensive disorders in pregnancy represent severe complications of pregnancy, which, if not treated, can result in serious health consequences for the mother and the child. Flavonoids are bioactive secondary metabolites commonly found in fruits, vegetables, green tea, whole grains, and medicinal plants. Flavonoids exert potent protective efficacy in experimental models of hypertensive disorders in pregnancy, especially preeclampsia, demonstrated through their capacity to modulate inflammatory responses, oxidative stress, and vascular dysfunction. In addition to their potential as therapeutics, flavonoids or flavonoid-rich food could be helpful to decrease the risk of hypertensive disorders in pregnancy when included in the diet pattern before and during pregnancy. However, the clinical evaluation of the potential capacity of flavonoids in hypertensive disorders in pregnancy is insufficient. Due to promising results from experimental studies, we highlight the need for the evaluation of flavonoids also in an appropriate clinical setting, which can be, together with proper preventive strategies, helpful in the overall management of hypertensive disorders in pregnancy.