Chemokine Fractalkine and Non-Obstructive Coronary Artery Disease-Is There a Link?

Non-obstructive coronary artery disease (NO-CAD) constitutes a heterogeneous group of conditions collectively characterized by less than 50% narrowing in at least one major coronary artery with a fractional flow reserve (FFR) of ≤0.80 observed in coronary angiography. The pathogenesis and progression of NO-CAD are still not fully understood, however, inflammatory processes, particularly atherosclerosis and microvascular dysfunction are known to play a major role in it. Chemokine fractalkine (FKN/CX3CL1) is inherently linked to these processes. FKN/CX3CL1 functions predominantly as a chemoattractant for immune cells, facilitating their transmigration through the vessel wall and inhibiting their apoptosis. Its concentrations correlate positively with major cardiovascular risk factors. Moreover, promising preliminary results have shown that FKN/CX3CL1 receptor inhibitor (KAND567) administered in the population of patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), inhibits the adverse reaction of the immune system that causes hyperinflammation. Whereas the link between FKN/CX3CL1 and NO-CAD appears evident, further studies are necessary to unveil this complex relationship. In this review, we critically overview the current data on FKN/CX3CL1 in the context of NO-CAD and present the novel clinical implications of the unique structure and function of FKN/CX3CL1 as a compound which distinctively contributes to the pathomechanism of this condition.

The cytokine trio - visfatin, placental growth factor and fractalkine - and their role in myocardial infarction with non-obstructive coronary arteries (MINOCA).

Myocardial infarction with nonobstructive coronary arteries (MINOCA) remains a puzzling clinical entity. It is characterized by clinical evidence of myocardial infarction (MI) with normal or near-normal coronary arteries in angiography. Given the complex etiology including multiple possible scenarios with varied pathogenetic mechanisms, profound investigation of the plausible biomarkers of MINOCA may bring further pathophysiological insights and novel diagnostic opportunities. Cytokines have a great diagnostic potential and are used as biomarkers for many diseases. An unusual trio of visfatin, placental growth factor (PlGF) and fractalkine (CX3CL1) can directly promote vascular dysfunction, inflammation and angiogenesis through the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. They are redundant in physiological processes and become overexpressed in the pathomechanisms underlying MINOCA. The knowledge about their concentration might serve as a valuable diagnostic and/or therapeutic tool for assessing vascular endothelial function. Here we analyze the current knowledge on visfatin, PlGF and CX3CL1 in the context of MINOCA and present the novel clinical implications of their combined expression as predictors or indicators of this condition.

Postprandial effect of gastrointestinal hormones and gastric activity in patients with irritable bowel syndrome.

Altered gut regulation, including motor and secretory mechanisms, is characteristic of irritable bowel syndrome (IBS). The severity of postprandial symptoms in IBS patients is associated with discomfort and pain; gas-related symptoms such as bloating and abdominal distension; and abnormal colonic motility. The aim of this study was to assess the postprandial response, i.e., gut peptide secretion and gastric myoelectric activity, in patients with constipation-predominant IBS. The study was conducted on 42 IBS patients (14 males, 28 females, mean age 45.1 ± 15.3 years) and 42 healthy participants (16 males, 26 females, mean age 41.1 ± 8.7 years). The study assessed plasma gut peptide levels (gastrin, CCK-Cholecystokinin, VIP-Vasoactive Intestinal Peptide, ghrelin, insulin) and gastric myoelectric activity obtained from electrogastrography (EGG) in the preprandial and postprandial period (meal-oral nutritional supplement 300 kcal/300 ml). Mean preprandial gastrin and insulin levels were significantly elevated in IBS patients compared to the control group (gastrin: 72.27 ± 26.89 vs. 12.27 ± 4.91 pg/ml; p < 0.00001 and insulin: 15.31 ± 12.92 vs. 8.04 ± 3.21 IU/ml; p = 0.0001), while VIP and ghrelin levels were decreased in IBS patients (VIP: 6.69 ± 4.68 vs. 27.26 ± 21.51 ng/ml; p = 0.0001 and ghrelin: 176.01 ± 88.47 vs. 250.24 ± 84.55 pg/ml; p < 0.0001). A nonsignificant change in the CCK level was observed. IBS patients showed significant changes in postprandial hormone levels compared to the preprandial state-specifically, there were increases in gastrin (p = 0.000), CCK (p < 0.0001), VIP (p < 0.0001), ghrelin (p = 0.000) and insulin (p < 0.0001). Patients with IBS showed reduced preprandial and postprandial normogastria (59.8 ± 22.0 vs. 66.3 ± 20.2%) compared to control values (83.19 ± 16.7%; p < 0.0001 vs. 86.1 ± 9.4%; p < 0.0001). In response to the meal, we did not observe an increase in the percentage of normogastria or the average percentage slow-wave coupling (APSWC) in IBS patients. The postprandial to preprandial power ratio (PR) indicates alterations in gastric contractions; in controls, PR = 2.7, whereas in IBS patients, PR = 1.7, which was significantly lower (p = 0.00009). This ratio reflects a decrease in gastric contractility. Disturbances in the postprandial concentration of gut peptides (gastrin, insulin and ghrelin) in plasma may contribute to abnormal gastric function and consequently intestinal motility, which are manifested in the intensification of clinical symptoms, such as visceral hypersensitivity or irregular bowel movements in IBS patients.

Microangiopathy in Naifold Videocapillaroscopy and Its Relations to sE- Selectin, Endothelin-1, and hsCRP as Putative Endothelium Dysfunction Markers among Adolescents with Raynaud's Phenomenon.

The aim of this study was to analyze the relationship between the qualitative abnormalities on nailfold videocapillaroscopy (NVC), and the concentrations of selected biomarkers (sE-selectin, endothelin-1, high-sensitivity c-reactive protein (hsCRP)) and lipid metabolism parameters in children and adolescents with Raynaud's phenomenon (RP). Raynaud's phenomenon, to assess whether nailfold capillary changes may reflect the degree of systemic blood vessel abnormalities. The study group included 66 patients (34 undifferentiated-uRP and 32 secondary-sRP) aged 6-19 years and the control group. In both groups, NVC was performed and the selected biomarkers were measured (sE-selectin, endothelin-1, hsCRP) and lipid profile. Endothelin-1, sE-selectin and hsCRP concentrations in patients from both RP groups were significantly higher; concentration of HDL fraction was significantly lower compared with the control group. The analysis of multiple linear regression demonstrated that megacapillaries most strongly determine the sE-selectin value (p = 0.04) and hsCRP (p = 0.03). Both the total cholesterol and low-density lipoprotein (LDL) fraction concentrations were determined by the presence of avascular areas (p = 0.02). In conclusion, specific pathologic NVC changes were associated with higher endothelial damage biomarkers concentration and adverse changes in the lipid profile.

Implementation of the modified four-step approach method for teaching echocardiography using the FATE protocol-A pilot study.

INTRODUCTION: Peyton's four-step approach is well-known and commonly used in medical education. It is a practical and useful method which is simple to apply. The study presents the implementation of the modified four-step approach method to teach how to perform the emergency echocardiographic assessment according to FATE (Focus-Assessed Transthoracic Echo) protocol. The aim of the study was to determine the feasibility and utility of this method FATE protocol teaching. DESIGN: We collected students' feedback relating to perception of this way of teaching. Based on a semistructured interview conducted with the students, as well as an evaluation of the electronic survey, it has been demonstrated that the four-step method is useful for teaching emergency echocardiographic assessment. SETTING: One Polish medical school. PARTICIPANTS: The classes were run in small groups as part of an elective ultrasound course for the fourth- and fifth-year students of the Faculty of Medicine of the Medical College. Twenty-two students were trained. RESULTS: Based on the opinions of the participants of the elective course and the teacher conducting the classes, which involved the use of the modified Peyton's four-step method in teaching echocardiography in emergency cases according to the FATE protocol, it has been determined that the four-step method is effective in imaging training. All participants claim that this method is clear and understandable. Advantages of the methodological approach: a slow-motion demonstration by the instructor, accompanied by the commentary on the activities undertaken and practical exercises performed by the participants, learning through repetition, requirement of constant concentration. CONCLUSIONS: Peyton's approach allows to use of the class time in maximal extend by consolidating new information and facilitating memorization through adequate instructor guidance and observation of the training of the peer students and repetition of the skills acquired.

How does preclinical laboratory training impact physical examination skills during the first clinical year? A retrospective analysis of routinely collected objective structured clinical examination scores among the first two matriculating classes of a reformed curriculum in one Polish medical school.

OBJECTIVE: As a result of a curriculum reform launched in 2012 at our institution, preclinical training was shortened to 2 years instead of the traditional 3 years, creating additional incentives to optimise teaching methods. In accordance with the new curriculum, a semester-long preclinical module of clinical skills (CS) laboratory training takes place in the second year of study, while an introductory clinical course (ie, brief introductory clerkships) is scheduled for the Fall semester of the third year. Objective structured clinical examinations (OSCEs) are carried out at the conclusion of both the preclinical module and the introductory clinical course. Our aim was to compare the scores at physical examination stations between the first and second matriculating classes of a newly reformed curriculum on preclinical second-year OSCEs and early clinical third-year OSCEs. DESIGN: Analysis of routinely collected data. SETTING: One Polish medical school. PARTICIPANTS: Complete OSCE records for 462 second-year students and 445 third-year students. OUTCOME MEASURES: OSCE scores by matriculation year. RESULTS: In comparison to the first class of the newly reformed curriculum, significantly higher (ie, better) OSCE scores were observed for those students who matriculated in 2013, a year after implementing the reformed curriculum. This finding was consistent for both second-year and third-year cohorts. Additionally, the magnitude of the improvement in median third-year OSCE scores was proportional to the corresponding advancement in preceding second-year preclinical OSCE scores for each of two different sets of physical examination tasks. In contrast, no significant difference was noted between the academic years in the ability to interpret laboratory data or ECG - tasks which had not been included in the second-year preclinical training. CONCLUSION: Our results suggest the importance of preclinical training in a CS laboratory to improve students' competence in physical examination at the completion of introductory clinical clerkships during the first clinical year.

1-Methylnicotinamide protects against liver injury induced by concanavalin A via a prostacyclin-dependent mechanism: A possible involvement of IL-4 and TNF-α.

We have recently demonstrated that concanavalin A (Con A)-induced hepatitis is associated with the release of endogenous 1-methylnicotinamide (MNA). Here we study the mechanism by which exogenous MNA alleviates Con A-induced liver inflammation and injury in vivo. The involvement of prostacyclin (PGI2) in hepatoprotective action of MNA (30-100 mg kg(-1); i.v.) was studied by the use of IP receptor antagonist RO3244794 (10 mg kg(-1); p.o.) given prior to Con A (5-20 mg kg(-1); i.v.). Liver damage was assessed by measurements of: liver specific transaminases in plasma (alanine aminotransferase; aspartate aminotransferase); cytokines release (IL-4, IFN-γ and TNF-α); liver histopathology; and 24h survival rates. Additionally, the effect of a stable analog of prostacyclin (carbaprostacyclin) on IL-4, IFN-γ and TNF-α production by isolated spleen lymphocytes in response to Con A was analyzed. MNA diminished Con A-induced rise in liver specific transaminases, alleviated histopathological injury and improved 24h survival rates, the latter effect in a degree comparable with the pretreatment of animals with dexamethasone (0.5 mg kg(-1); i.p.). MNA inhibited also a rise in IL-4 and TNF-α concentration in plasma measured 2 h after Con A administration, while IFN-γ was less affected. The effects of MNA were reversed by pretreatment with IP antagonist RO3244794. In isolated spleen lymphocytes, carbaprostacyclin profoundly decreased production of IL-4, the effect on TNF-α was modest with no effect on IFN-γ production. In conclusion, MNA attenuated Con A-induced hepatitis by a prostacyclin-dependent mechanism involving the inhibition of lymphocytes-derived IL-4 and the inhibition of Kuppfer-cells derived TNF-α.

[Analysis of lifestyle and risk factors of atherosclerosis in students of selected universities in Krakow].

Introduction: Reduction of risk factors of atherosclerosis, lifestyle modification significantly cause the reduction in the incidence, morbidity and mortality of cardiovascular diseases (CVDs). Objective: To evaluate cardiovascular risk factors and analyze the lifestyle of students finishing the first year of studies at selected universities in Krakow. Material and Methods: The study was performed in 2015roku. 566 students finishing the first year of study, including 319 (56.4%) men and 247 (43.6%) women were examined. The students were in age from 18 to 27 years, an average of 20.11± 1.15 years. They represented 6 different universities in Cracow. In order to assess eating habits, lifestyle and analysis of risk factors of cardiovascular disease was used method of diagnostic survey using the survey technique. BMI was calculated from anthropometric measurements. The program Statistica 12.0 were used in statistical analysis. Results: The analysis showed that most fruits and vegetables consume UR students and AWF, least of AGH. Only 34.8% of students regularly consume fish of the sea, there were no significant differences between universities. Sports frequently cultivate the students of AWF (93% of the students of this university). Academy of Fine Arts students drink the most coffee. Students of AGH frequently consume alcohol. 60% of all students never tried drugs, but only 25.7% of student of Fine Arts never tried drugs. Overweight occurs in 12.6% of students, and obesity in 1.1%. Conclusions: The most risk factors of atherosclerosis occur in students of AGH and ASP. The results of the study clearly indicate on the necessity of implementation of prevention and improvement of health behaviors in students of AGH and ASP universities.

TGF-ß1 and granulocyte elastase in the evaluation of activity of inflammatory bowel disease. A pilot study.

INTRODUCTION: The aim was to assess the usefulness of TGF-ß1 and elastase in the evaluation of activity of ulcerative colitis (UC) and Crohn's disease (CD). MATERIAL AND METHODS: 32 patients diagnosed with UC, 31 with CD and 30 healthy volunteers were enrolled in this study. Diagnosis of the disease was confirmed by videocolonoscopy and histopathological evaluation of intestinal biopsies. Disease activity was assessed by use of the Mayo Scoring System for Assessment of Ulcerative Colitis Activity in UC patients and by CDAI in CD patients. hsCRP was determined by the immunonephelometric method, TGF-ß1 and elastase plasma concentration by ELISA. The results of the study were analyzed using Statistica and R statistical language. RESULTS: In UC a positive correlation between disease activity and platelet level, hsCRP and TGF-ß1 concentration was noted. Elastase concentration in UC patients was significantly higher than in CD, but there was no correlation with the activity of the disease. In CD patients we observed a positive correlation between disease activity and leukocytes, platelet levels and elastase concentration, and a very low correlation with hsCRP and TGF-ß1. DISCUSSION: Determination of TGF-ß1 can be used for evaluation of inflammatory activity in UC and it is connected with elevated concentrations of CRP and platelets. To a lower extent TGF-ß1 can also be used for evaluation of inflammatory activity in CD. Examination of elastase concentration may be useful in the assessment of CD activity. Plasma elastase concentration may be helpful in UC and CD differentiation. The preliminary results of this investigation seem promising; nevertheless, more studies are necessary.

Autonomic nervous system activity in constipation-predominant irritable bowel syndrome patients.

BACKGROUND: The main mechanism underlying irritable bowel syndrome is currently believed to be a dysfunction of the brain-gut axis. Autonomic nervous system dysfunction can contribute to development of irritable bowel syndrome symptoms by disturbing visceral sensations. MATERIAL/METHODS: Thirty patients with a diagnosis of constipation-predominant irritable bowel syndrome and 30 healthy volunteers were included in the study. Resting and functional autonomic nervous system tests and percutaneous electrogastrography were performed. Plasma adrenalin, noradrenalin, insulin, ghrelin and cholecystokinin activity was analyzed. RESULTS: Increased sympathetic activation with disturbed parasympathetic function was demonstrated. Patients had substantially higher plasma catecholamine concentration, which confirms sympathetic overbalance. Hyperinsulinemia may explain sympathetic predominance followed by gastric and intestinal motility deceleration. Abnormal, reduced ghrelin and cholecystokinin titre may disturb brain-gut axis functioning and may be responsible for gastric motility deceleration. In electrogastrography, distinctly lower values of fasting normogastria percentage and dominant power were observed. Patients had substantially lower slow wave coupling percentage both in fasting and postprandial periods, which negatively correlated with plasma catecholamines level. Gastric myoelectrical activity disturbances may result from lack of sympatho-parasympathetic equilibrium. CONCLUSIONS: Central sympathetic influence within the brain-gut axis is most probably responsible for myoelectrical activity disturbances in irritable bowel syndrome patients.

Activated thrombin activatable fibrinolysis inhibitor (TAFIa) is associated with inflammatory markers in inflammatory bowel diseases TAFIa level in patients with IBD.

BACKGROUND: Thrombin activatable fibrinolysis inhibitor (TAFI) has been reported to be involved in the pathogenesis and progression of inflammatory bowel disease (IBD). Activated TAFI (TAFIa) attenuates fibrinolysis by cleaving C-terminal lysine residues thus down-regulating plasminogen activation. To date, no reports on TAFIa in IBD have been published. METHODS: Plasma levels of TAFIa were measured using a functional assay in 55 consecutive patients with ulcerative colitis (UC) and 50 with Crohn's disease (CD). Associations of TAFIa with disease activity, hemostatic variables and inflammatory markers were assessed. RESULTS: Plasma TAFIa was higher in CD patients than in those with UC. The disease activity correlated positively with TAFIa levels in the UC group, but not in the CD group. In UC patients, there were positive correlations of TAFIa with white blood cells, C-reactive protein and fibrinogen and an inverse correlation with albumin. In the CD group, a positive correlation was shown for C-reactive protein, fibrinogen and platelet count, while a negative correlation was noted for albumin. CONCLUSIONS: This study is the first to show that TAFIa is increased in CD patients compared with UC and its levels are associated with inflammatory markers in both forms of IBD. These findings fit in the hypothesis that TAFIa may be a marker of active IBD, and in particular of active UC.

[Morphological changes of the colon in patients with irritable bowel syndrome]. / Zmiany morfologiczne jelita grubego u osób z zespolem jelita drazliwego.

INTRODUCTION: Irritable bowel syndrome (IBS) is a common disease belonging to the group of chronic functional gastrointestinal disorders. Variety of symptoms and lack of macroscopic and structural pathologies in colon, make IBS a challenge both in diagnosis and in medication. According to the last reports, the role of chronic minimal inflammation in colon mucosa is becoming more relevant. AIMS: The aim of this study was to verify the microscopic and macroscopic changes in colon mucosa in patients with IBS. METHODS: A retrospective study of microscopic changes and macroscopic lesions in colon, due to endoscopy biopsies in the group of 89 patients diagnosed with IBS in an average age of 47 years. RESULTS: Mild inflammation of colonic mucosa in lamina propria was observed in 92% patients, 34% presented other inflammatory cells. No statistical relationship between macroscopic lesions (in 44% cases) and lymphatic infiltration was observed. CONCLUSIONS: Low grade inflammation of lamina propria in colon was observed among patients with IBS. Beside the edema of the lamina propria, no correlation between macroscopic and microscopic changes was found. Despite the fact that IBS is a functional disorder, in many patients occur morphological changes in colon mucosa. Further studies are necessary.

Myoelectric and autonomic nervous system activity in patients with irritable bowel syndrome.

Explanation of the main causes of symptoms and dysfunctions in the FGIDs is focused on visceral hypersensitivity. Sympathetic stimulation increases sensitivity of visceral receptors. Thus overall influences of the autonomic nervous system are important not only in regulation of secretion and motility of the gastrointestinal tract but also in visceral sensation. The aim of this study was to evaluate gastric motility disturbances and changes in the autonomic nervous system (ANS) activity in irritable bowel syndrome patients (IBS). Our results show changes of the autonomic system activity in patients with IBS: decreased parasympathetic and increased sympathetic activity. The patients with autonomic dysfunction had also high percentage of dysrrhythmia time. We conclude that dyspeptic symptoms in patients with autonomic dysfunction are caused mostly by high adrenergic drive resulting in dysrrhythmias and decrease in the EGG amplitude.