Autoantibodies in Wilson disease: Impact on clinical course.

Symptoms of Wilson disease (WD) vary and additional factors such as autoimmunity may play an important role in WD pathogenesis. The presence of antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies, neuronal surface antibodies, and onconeural antibodies in WD was investigated using standardized indirect immunofluorescence assays and Western Blot analysis. The presence of all studied autoantibodies was higher in WD patients in comparison to healthy subjects, but there was no statistically significant difference in autoantibodies frequency according to disease manifestation. D-penicillamine treatment was associated with a higher presence of ANA than zinc sulfate but without an increase in autoimmune diseases rate.

Characterization of the SGLT2 Interaction Network and Its Regulation by SGLT2 Inhibitors: A Bioinformatic Analysis.

Background: Sodium-glucose cotransporter 2 (SGLT2), also known as solute carrier family 5 member 2 (SLC5A2), is a promising target for a new class of drugs primarily established as kidney-targeting, effective glucose-lowering agents used in diabetes mellitus (DM) patients. Increasing evidence indicates that besides renal effects, SGLT2 inhibitors (SGLT2i) have also a systemic impact via indirectly targeting the heart and other tissues. Our hypothesis states that the pleiotropic effects of SGLT2i are associated with their binding force, location of targets in the SGLT2 networks, targets involvement in signaling pathways, and their tissue-specific expression. Methods: Thus, to investigate differences in SGLT2i impact on human organisms, we re-created the SGLT2 interaction network incorporating its inhibitors and metformin and analyzed its tissue-specific expression using publicly available datasets. We analyzed it in the context of the so-called key terms ( autophagy, oxidative stress, aging, senescence, inflammation, AMPK pathways, and mTOR pathways) which seem to be crucial to elucidating the SGLT2 role in a variety of clinical manifestations. Results: Analysis of SGLT2 and its network components' expression confidence identified selected organs in the following order: kidney, liver, adipose tissue, blood, heart, muscle, intestine, brain, and artery according to the TISSUES database. Drug repurposing analysis of known SGLT2i pointed out the influence of SGLT1 regulators on the heart and intestine tissue. Additionally, dapagliflozin seems to also have a stronger impact on brain tissue through the regulation of SGLT3 and SLC5A11. The shortest path analysis identified interaction SIRT1-SGLT2 among the top five interactions across six from seven analyzed networks associated with the key terms. Other top first-level SGLT2 interactors associated with key terms were not only ADIPOQ, INS, GLUT4, ACE, and GLUT1 but also less recognized ILK and ADCY7. Among other interactors which appeared in multiple shortest-path analyses were GPT, COG2, and MGAM. Enrichment analysis of SGLT2 network components showed the highest overrepresentation of hypertensive disease, DM-related diseases for both levels of SGLT2 interactors. Additionally, for the extended SGLT2 network, we observed enrichment in obesity (including SGLT1), cancer-related terms, neuroactive ligand-receptor interaction, and neutrophil-mediated immunity. Conclusion: This study provides comprehensive and ranked information about the SGLT2 interaction network in the context of tissue expression and can help to predict the clinical effects of the SGLT2i.

The role of non-coding RNAs in neuroinflammatory process in multiple sclerosis.

Multiple sclerosis (MS) is a central nervous system chronic neuroinflammatory disease followed by neurodegeneration. The diagnosis is based on clinical presentation, cerebrospinal fluid testing and magnetic resonance imagining. There is still a lack of a diagnostic blood-based biomarker for MS. Due to the cost and difficulty of diagnosis, new and more easily accessible methods are being sought. New biomarkers should also allow for early diagnosis. Additionally, the treatment of MS should lead to the personalization of the therapy. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) as well as their target genes participate in pathophysiology processes in MS. Although the detailed mechanism of action of non-coding RNAs (ncRNAs, including miRNAs and lncRNAs) on neuroinflammation in MS has not been fully explained, several studies were conducted aiming to analyse their impact in MS. In this article, we review up-to-date knowledge on the latest research concerning the ncRNAs in MS and evaluate their role in neuroinflammation. We also point out the most promising ncRNAs which may be promising in MS as diagnostic and prognostic biomarkers.

High concentration of symmetric dimethylarginine is associated with low platelet reactivity and increased bleeding risk in patients with acute coronary syndrome.

BACKGROUND: Dual antiplatelet therapy (DAPT) prevents ischemic events in patients with acute coronary syndrome (ACS), but is associated with increased risk of bleeding events. Symmetric dimethylarginine (SDMA) is one of nitric oxide (NO)-related pathway metabolites and stands as a promising biomarker of early chronic kidney disease (CKD) and cardiovascular diseases (CVDs). OBJECTIVES: Our study evaluated the role of SDMA in predicting bleeding events in patients after ACS treated with DAPT. METHODS: We compared plasma concentrations of NO-related pathway metabolites in patients with ACS (n = 291) and investigated the prognostic value of SDMA as a bleeding predictor during 1-year follow-up. We measured the metabolites concentration using ultra performance liquid chromatography. Platelet reactivity was determined using impedance aggregometry. RESULTS: Patients with the highest quartile (4th) of SDMA concentration had significantly lower platelet aggregation compared to those in the 1st-3rd quartiles of SDMA, based on ADP + PGE1-, AA-, and ADP-induced platelet reactivity tests (p = 0.0004, p = 0.002, p = 0.014, respectively). Patients with major or minor bleeding events had significantly higher concentrations of SDMA as compared to those without bleeding events or to those with minimal bleeding events (p = 0.019, p = 0.019, respectively). CONCLUSION: Higher SDMA concentration is associated with lower platelet reactivity and is associated with major and minor bleeding events in patients with ACS on DAPT. Therefore, SDMA stands as a potential biomarker for individualization of duration and potency of antiplatelet therapies in the ACS population at high risk of bleeding complications.

The role of miRNAs in regulation of platelet activity and related diseases - a bioinformatic analysis.

MicroRNAs (miRNAs) are small, non-coding RNAs, able to regulate cellular functions by induction of mRNA degradation and post-transcriptional repression of gene expression. Platelets are the major source of circulating miRNAs, with significant regulatory potential on cardiovascular pathophysiology and other diseases. MiRNAs have been shown to modify the expression of platelet proteins, which influence the platelets reactivity. Circulating miRNAs can be determined from plasma, serum, or whole blood, and they can be used as diagnostic and prognostic biomarkers as well as therapeutic targets including cardiovascular diseases (CVDs). Herein, we present original results from bioinformatic analyses, which identified top 22 platelet-related miRNAs including hsa-miR-320a, hsa-miR-16-5p, hsa-miR-106a-5p, hsa-miR-320b, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-195-5p, hsa-miR-92a-3p as widely involved in platelet reactivity and associated diseases, including CVDs, Alzheimer's and cerebrovascular diseases, cancer and hypertension. Analysis focused on the identification of the highly regulatory targets shared between those miRNAs identified 43 of them. Best ranked genes associated with overall platelet activity and most susceptible for noncoding regulation were PTEN, PIK3R1, CREB1, APP, and MAPK1. Top targets also strongly associated with CVDs were VEGFA, IGF1, ESR1, BDNF, and PPARG. Top targets associated with other platelet-related diseases including cancer identified in our study were TP53, KRAS, and CCND1. The most affected pathways by top miRNAs and top targets included diseases of signal transduction by Growth Factor Receptors (GDFRs) and second messengers, platelet activation, signaling, and aggregation, signaling by VEGF, MAPK family signaling cascades, and signaling by Interleukins. Terms specific only for platelet-related miRNAs included coronary artery disease, platelet degranulation, and neutrophil degranulation, while for the top platelet-related genes it was Estrogen Signaling Receptor (ESR) mediated signaling, extra-nuclear estrogen signaling, and endometriosis. Our results show the novel features of platelet physiology and may provide a basis for further clinical studies focused on platelet reactivity. They also show in which aspects miRNAs can be promising biomarkers of platelet-related pathological processes.

Antiplatelet drugs and liver fibrosis.

Liver fibrosis results from an imbalance between extracellular matrix formation and degradation. The background of liver fibrosis is chronic inflammation and subsequent microcirculation disturbance including microthrombosis. Platelets actively participate in liver fibrosis not only as a part of the clotting system but also by releasing granules containing important mediators. In fact, platelets may play a dual role in the pathophysiology of liver fibrosis as they are able to stimulate regeneration as well as aggravate the destruction of the liver. Recent studies revealed that antiplatelet therapy correlates with inhibition of liver fibrosis. However, liver impairment is associated with extensive coagulation disorders thus the safety of antiplatelet therapy is an area for detailed exploration. In this review, the role of platelets in liver fibrosis and accompanying hemostatic disorders are discussed. Additionally, results of animal and human studies on antiplatelet drugs in liver disorders and their potential therapeutic utility are presented.

Plasma Trimethylamine-N-Oxide Is an Independent Predictor of Long-Term Cardiovascular Mortality in Patients Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndrome.

To investigate the association of liver metabolite trimethylamine N-oxide (TMAO) with cardiovascular disease (CV)-related and all-cause mortality in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention. Our prospective observational study enrolled 292 patients with ACS. Plasma concentrations of TMAO were measured during the hospitalization for ACS. Observation period lasted seven yr in median. Adjusted Cox-regression analysis was used for prediction of mortality. ROC curve analysis revealed that increasing concentrations of TMAO levels assessed at the time point of ACS significantly predicted the risk of CV mortality (c-index=0.78, p < 0.001). The cut-off value of >4 µmol/L, labeled as high TMAO level (23% of study population), provided the greatest sum of sensitivity (85%) and specificity (80%) for the prediction of CV mortality and was associated with a positive predictive value of 16% and a negative predictive value of 99%. A multivariate Cox regression model revealed that high TMAO level was a strong and independent predictor of CV death (HR = 11.62, 95% CI: 2.26-59.67; p = 0.003). High TMAO levels as compared with low TMAO levels were associated with the highest risk of CV death in a subpopulation of patients with diabetes mellitus (27.3 vs. 2.6%; p = 0.004). Although increasing TMAO levels were also significantly associated with all-cause mortality, their estimates for diagnostic accuracy were low. High TMAO level is a strong and independent predictor of long-term CV mortality among patients presenting with ACS.

Intraosseous vascular access in emergency and trauma settings: a comparison of the most universally used intraosseous devices.

Introduction: Obtaining successful vascular access is an essential component of the emergency and trauma setting. The modern practice of medicine advocates IO access for patients in a critical condition, especially when IV access is problematic or unobtainable. Various medical devices allowing for IO access have been coined and used in the management of critical patients.Areas covered: This study aims to review the literature regarding different intraosseous devices used to obtain vascular access (Bone Injection Gun (BIG), EZ-IO, NIO, Jamshidi, and First Access for Shock and Trauma (FAST-1) and discuss their clinical and experimental role in the emergency and trauma settings.Expert opinion: The development of medical technology contributes to an increasing number of intraosseous devices facilitating vascular access in challenging scenarios, including cardiopulmonary resuscitation, anaphylactic, or hypovolemic shock. Each of these devices provides an effective route for fluid resuscitation, drug delivery, laboratory evaluation, and shortening the timeframe for established vascular access, provided that the person obtaining the access is acquainted with the use of the device.

Factors predicting clinical outcomes from 494 vitrified oocyte donation cycles at a UK-regulated egg bank.

RESEARCH QUESTION: Do donor age, AMH, AFC, BMI and reproductive history predict response to ovarian stimulation? Do donor and recipient clinical markers and embryology parameters predict recipient pregnancy and live birth? DESIGN: Retrospective cohort study of 494 altruistic oocyte donors aged 18-35 years; 340 were matched to 559 recipients. Predictors of donor total oocyte yield and total mature oocyte yield were identified. Total and mature oocyte number were compared according to stratified donor AMH and age. Donor, recipient and embryology parameters predictive of recipient primary outcomes (clinical pregnancy and live birth) were identified. RESULTS: Donor age and AMH predicted total oocyte yield (P = 0.030 and P < 0.001)) and total mature oocyte yield (P = 0.011 and P < 0.001). Donors aged 30-35 years with AMH 15-29.9 pmol/l had lower total oocyte yield (P = 0.004) and mature oocyte yield (P < 0.001) than donors aged 18-24 years. Up to an AMH threshold of 39.9 pmol/l, increasing AMH levels predicted higher total oocyte yield (<15 pmol/l versus 15-29.9 pmol/l, P = 0.001; 15-29.9 pmol/l versus 30-39.9 pmol/l, P < 0.001; 30-39.9pmol/l versus ≥ 40 pmol/l, P = 1.0) and mature oocyte yield (<15 pmol/l versus 15-29.9 pmol/l, P = 0.005; 15-29.9 pmol/l versus 30-39.9 pmol/l, P = 0.006; 30-39.9 pmol/l versus ≥40 pmol/l, P = 1.0). In recipients, the rate of transferrable embryos per oocytes received, fertilized and number of embryo transfers needed to achieve the primary outcome were predictors of cumulative clinical pregnancy (P = 0.011, P = 0.017 and P < 0.001) and live birth (P = 0.008, P = 0.012 and P < 0.001) rates. Recipient BMI (P = 0.024) and previous miscarriages (P = 0.045) were predictors of cumulative live birth rate. Donor age 18-22 years was associated with a lower incidence of recipient clinical pregnancy (P = 0.004) and live birth (P = 0.001) after the first embryo transfer versus donor age 23-29 years. CONCLUSIONS: Donor age and AMH are independent predictors of oocyte yield. Raised recipient BMI and history of miscarriages reduce cumulative live birth rates, which may be increased by selecting donors aged 23-29 years, instead of younger donors.

Long Non-coding RNAs as Promising Therapeutic Approach in Ischemic Stroke: a Comprehensive Review.

In recent years, ischemic stroke (IS) has been one of the major causes of disability and mortality worldwide. The general mechanism of IS is based on reduced blood supply to neuronal tissue, resulting in neuronal cell damage by various pathological reactions. One of the main techniques for acute IS treatment entails advanced surgical approaches for restoration of cerebral blood supply but this is often associated with secondary brain injury, also known as ischemic reperfusion injury (I/R injury). Many researches have come to emphasize the significant role of long non-coding RNAs (lncRNAs) in IS, especially in I/R injury and their potential as therapeutic approaches. LncRNAs are non-protein transcripts that are able to regulate cellular processes and gene expression. Further, lncRNAs have been shown to be involved in neuronal signaling pathways. Several lncRNAs are recognized as key factors in the physiological and pathological processes of IS. In this review, we discuss the role of lncRNAs in neuronal injury mechanisms and their association with brain neuroprotection. Moreover, we identify the lncRNAs that show the greatest potential as novel therapeutic approaches in IS, which therefore merit further investigation in preclinical research. Graphical Abstract.

The Importance of Non-Coding RNAs in Neurodegenerative Processes of Diabetes-Related Molecular Pathways.

Diabetes mellitus (DM) is a complex condition and serious health problem, with growing occurrence of DM-associated complications occurring globally. Persistent hyperglycemia is confirmed as promoting neurovascular dysfunction leading to irreversible endothelial cell dysfunction, increased neuronal cell apoptosis, oxidative stress and inflammation. These collaboratively and individually result in micro- and macroangiopathy as well as neuropathy demonstrated by progressive neuronal loss. Recently, major efforts have been pursued to select not only useful diagnostic and prognostic biomarkers, but also novel therapeutic approaches. Both microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) belong to a class of non-coding RNAs identified in most of the body fluids i.e., peripheral blood, cerebrospinal fluid, brain tissue and neurons. Numerous miRNAs, lncRNAs and their target genes are able to modulate signaling pathways known to play a role in the pathophysiology of progressive neuronal dysfunction. Therefore, they pose as promising biomarkers and treatment for the vast majority of neurodegenerative disorders. This review provides an overall assessment of both miRNAs' and lncRNAs' utility in decelerating progressive nervous system impairment, including neurodegeneration in diabetic pathways.

MicroRNAs and Long Noncoding RNAs in Coronary Artery Disease: New and Potential Therapeutic Targets.

Noncoding RNAs (ncRNAs), including long noncoding RNAs and microRNAs, play an important role in coronary artery disease onset and progression. The ability of ncRNAs to simultaneously regulate many target genes allows them to modulate various key processes involved in atherosclerosis, including lipid metabolism, smooth muscle cell proliferation, autophagy, and foam cell formation. This review focuses on the therapeutic potential of the most important ncRNAs in coronary artery disease. Moreover, various other promising microRNAs and long noncoding RNAs that attract substantial scientific interest as potential therapeutic targets in coronary artery disease and merit further investigation are presented.

Secondary cervical cancer prevention in routine prenatal care - coverage, results and lessons for the future.

OBJECTIVES: Cervical cancer is the fourth most common type of cancer among women worldwide and one of the most common malignancies diagnosed in gravidas. Therefore, routine antenatal Pap smear is such an important examination. The aim of the study was to assess the prevalence of Pap smear performance during prenatal care and to determine possible factors affecting it. MATERIAL AND METHODS: A self-composed questionnaire was distributed among 638 women managed in a tertiary obstetric referral center. 33 questions regarded cervical cancer prevention and risk factors. RESULTS: 96.9% of respondents had undergone Pap smear and 80.6% had it performed during pregnancy. For 11.5% women Pap smear in pregnancy was the first one in their life. The most common reasons for lack of Pap smear performance were: no subjective need to perform it (40.9%), no doctor's recommendation (28.6%) and lack of gynecological care (16.3%). Among professionally active women the percentage of those who had not undergone Pap smear during pregnancy was statistically higher (28.5%) than among those who were on sick leave (13.5%) (p = 0.0003). Also, younger women were at risk of less frequent participation in cervical cancer screening CONCLUSIONS: Although performance of Pap smear among surveyed patients was relatively high, there was a significant group of women who had undergone their first test during pregnancy, which makes secondary cervical cancer prevention in prenatal care a useful prophylactic strategy. Special attention should be given to younger and professionally active women.