The Correlation of Serum Calpain 1 Activity and Concentrations of Interleukin 33 in COVID-19 Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is one of the most severe complications of the COVID-19 disease. The role of IL-33 and calpain 1 was previously described in lung infections and lung tissue damage. Our study examined the association between serum calpain 1 activity and IL-33 concentration in patients with COVID-19 ARDS. In the research, we included 80 subjects who had COVID-19 pneumonia and divided them into 2 groups: 40 subjects with ARDS and 40 subjects without ARDS. The basis of the research was the collection of subjects' data and the sampling of peripheral venous blood. The concentration of IL-33 was determined by the ELISA method and the activity of calpain 1 by the fluorometry method. Our research showed elevated calpain 1 activity and IL-33 concentration in the serum of COVID-19 patients who developed ARDS compared to those who did not develop ARDS and a positive correlation between them was established. Further, a positive correlation was established between the examined parameters and the severity of the disease, proinflammatory markers, and the use of mechanical ventilation. These results indicate a possible association and role of calpain 1 and IL-33 with the development of ARDS in COVID-19 patients.

COVID-19 pandemic: Impact on the cardiac implantable electronic devices' implantation rates in Croatia.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) pandemic has influenced health-care organization worldwide, including management of non-communicable diseases. The aim of this study was to determine the impact of COVID-19 pandemic on cardiac implantable electronic devices' (CIEDs) implantation rates in Croatia. METHODS: A retrospective, observational, national study was conducted. The data on CIEDs' implantation rates from 20 Croatian implantation centres, between January 2018 and June 2021, were extracted from the national Health Insurance Fund registry. Implantation rates before and after COVID-19 pandemic started, were compared. RESULTS: The overall numbers of CIED implantations in Croatia during COVID-19 pandemic were not different in comparison to 2 years pre-COVID-19 time (2618 vs. 2807, p = .081). The pacemaker implantation rates decreased significantly (by 45%) during April (122 vs. 223, p < .001) and May 2020 (135 vs. 244, p = .001), as well as during November 2020 (177 vs. 264, p = .003), but significantly increased during summer months 2020 comparing to 2018 and 2019 (737 vs. 497, p<0.001). The ICD implantation rates decreased significantly by 59% in April 2020 (26 vs. 64, p = .048). CONCLUSION: To the authors best knowledge this is a first study including complete national data on CIED implantation rates and COVID-19 pandemic impact. A significant reduction in number of both pacemaker and ICD implants during specific months of the COVID-19 pandemic was determined. However, afterwards compensation in implants resulted in similar total number when the complete year was evaluated.

The Relationship of Left Ventricular Diastolic Dysfunction and Asymmetrical Dimethylarginine as a Biomarker of Endothelial Dysfunction with Cardiovascular Risk Assessed by Systematic Coronary Risk Evaluation2 Algorithm and Heart Failure-A Cross-Sectional Study.

Background: Cardiovascular (CV) risk factors, causing endothelial dysfunction (ED) and left ventricular diastolic dysfunction (LVDD), contribute to an increased risk of heart failure (HF). The aim of this study was to determine the relationship between the occurrence of LVDD and ED with CV risk assessed by the Systematic Coronary Risk Evaluation2 (SCORE2) algorithm and HF. Methods: In the period from November 2019 to May 2022, a cross-sectional study that included 178 middle-aged adults was conducted. Transthoracic echocardiography (TTE) was used to assess left ventricular (LV) diastolic and systolic function. ED was assessed using the plasma values of asymmetric dimethylarginine (ADMA) and was determined using the ELISA method. Results: The majority of subjects with LVDD grades 2 and 3 had high/very high SCORE2, developed HF and all were taking medication (p < 0.001). They also had significantly lowest plasma ADMA values (p < 0.001). We found that the reduction of ADMA concentration is influenced by certain groups of drugs, or more significantly, by their combinations (p < 0.001). Conclusions: In our study, we confirmed a positive correlation between LVDD, HF and SCORE2 severity. The results showed a negative correlation between the biomarkers of ED, LVDD severity, HF, and SCORE2, which we believe is due to medication effects.

The Relationship between Nrf2 and HO-1 with the Severity of COVID-19 Disease.

Nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) have significant roles in the development of a hyperinflammatory state in infectious diseases. We aimed to investigate the association of the serum concentrations of Nrf2 and HO-1 with the severity of COVID-19 disease. The study included 40 subjects with mild and moderately severe forms of the disease (MEWS scoring system ≤2). Twenty of the subjects had MEWS scores of 3 or 4, which indicate a severe form of the disease, and twenty subjects had a MEWS score of ≥5, which indicates a critical form of the disease. HO-1 and Nrf2 were measured using the commercially available Enzyme-Linked Immunosorbent Assay (ELISA). Subjects with the most severe form of COVID-19 (critically ill) had a lower concentration of Nrf2 that negatively correlated with the markers of hyperinflammatory response (CRP, IL-6, ferritin). This observation was not made for HO-1, and the correlation between Nrf2 and HO-1 values was not established. In the mild/moderate form of COVID-19 disease, Nrf2 was associated with an increased 1,25 dihydroxy vitamin D concentration. The results of this study show that Nrf2 has a role in the body's anti-inflammatory response to COVID-19 disease, which makes it a potential therapeutic target.

The Role of Extracorporeal Blood Purification in the Treatment of a Patient with Lemierre's Syndrome.

Lemierre's syndrome refers to the septic thrombophlebitis of the internal jugular vein. The condition typically begins with an oropharyngeal infection and frequently involves inflammation within the wall of the vein, infected thrombus within the lumen, surrounding soft tissue inflammation, persistent bacteremia, and septic emboli. Lemierre's syndrome is a rare disease; it occurs most commonly in otherwise healthy young adults. The most common etiologic agent is Fusobacterium necrophorum. We present a case of Lemierre's syndrome in a young girl and the role of extracorporeal method of blood purification with continuous venous hemodiafiltration with the use of a highly adsorptive membrane (AN69 HeprAN), thus achieving the combined elimination of cytokines and endotoxins. The use of advanced methods, along with an antibiotic and surgical treatment, will certainly help reduce mortality in this syndrome.

Understanding the association between endothelial dysfunction and left ventricle diastolic dysfunction in development of coronary artery disease and heart failure.

Cardiovascular diseases (CVDs)  have been the most common cause of death worldwide for decades. Until recently the most affected patients were middle-aged and elderly, predominantly men, with more frequent ST elevation myocardial infarction  (STEMI) caused by obstructive coronary artery disease (CAD). However, in the last two decades we have noticed an increased incidence of ischemia with non-obstructive coronary arteries (INOCA), which includes myocardial infarction with non-obstructive coronary arteries (MINOCA) and non-myocardial infarction syndromes, such as microvascular and vasospastic angina, conditions that have been particularly pronounced in women and young adults - the population we considered low-risky till than. Therefore, it has become apparent that for this group of patients conventional methods of assessing the risk of future cardiovascular (CV) events are no longer specific and sensitive enough. Heart failure with preserved ejection fraction (HFpEF) is another disease, the incidence of which has been rising rapidly during last two decades, and predominantly affects elderly population. Although the etiology and pathophysiology of INOCA and HFpEF are complex and not fully understood, there is no doubt that the underlying cause of both conditions is endothelial dysfunction (ED) which further promotes the development of left ventricular diastolic dysfunction (LVDD). Plasma biomarkers of ED, as well as natriuretic peptides (NPs), have been intensively investigated recently, and some of them have great potential for early detection and better assessment of CV risk in the future.

Perindopril/amlodipine-induced thrombotic microangiopathy.

This is the first report on a case of perindopril/amlodipine-induced thrombotic microangiopathy (TMA) syndrome. A 48-year-old female was admitted complaining of nettle rash all over the body, bloody urine, and weakness shortly after starting antihypertensive therapy with perindopril/amlodipine. Shortly thereafter, she developed pronounced hemiparesis, somnolence, and sensorimotor aphasia. Laboratory findings were compatible with microangiopathic hemolytic anemia and thrombocytopenia. She was diagnosed with TMA. Cessation of perindopril/amlodipine therapy and treatment with plasma exchange and systemic corticosteroids resulted in full recovery. Very seldom perindopril/amlodipine may cause hematologic abnormalities, probably through an immunological mechanism, but there were no reports of causing TMA so far. In our case, the symptoms began shortly after the start of perindopril/amlodipine use. The clinical course of TMA in the case was compatible with TMA related to an acute, immune-mediated drug reaction. The most important thing is to promptly recognize TMA and its induction by a drug because distinctive treatment and cessation of the suspected drug can prevent severe outcome, as it was avoided in our patient.

Serum carbohydrate sulfotransferase 7 in lung cancer and non-malignant pulmonary inflammations.

BACKGROUND: Carbohydrate sulfotransferases (CHST) were shown to be involved in carcinogenesis. The aim of the study was to assess the diagnostic value of serum CHST7 concentration in differentiation between lung cancer and non-malignant pulmonary inflammations. METHODS: Clinical case-control study involving 125 participants was conducted: the control group containing cases of pneumonia and chronic obstructive pulmonary disease was compared to the lung cancer group composed of primary and metastatic cancers. Serum concentrations of CHST7 and routinely used markers including carcinoembryonic antigen (CEA), cytokeratin fragment 21-1 (CYFRA 21-1) and neuron-specific enolase (NSE) were determined for each participant using immunochemical methods. Statistical association, receiver operating characteristic (ROC) analysis and cross-validation were used for the evaluation of CHST7 either as a standalone biomarker or as a part of a biomarker panel. RESULTS: In comparison to the control group, serum CHST7 was elevated in lung cancer (p<0.001), but no differences between the overall stages of primary cancers were detected (p=0.828). The differentiation performance in terms of ROC area under curve (AUC) was 0.848 making CHST7 superior biomarker to the NSE (p=0.031). In comparison to CEA and CYFRA 21-1, the performance differences were not detected. CHST7 was not correlated to other biomarkers, and its addition to the routine biomarker panel significantly improved the cross-validated accuracy (85.6% vs. 75.2%) and ROC AUC (p=0.004) of the differentiation using a machine learning approach. CONCLUSIONS: Serum CHST7 is a promising biomarker for the differentiation between lung cancer and non-malignant pulmonary inflammations.

Case Report: Surgical Treatment of Two Asymptomatic Myxomas at Two Atypical Locations.

Atypical presentation of myxomas in the two cases described here arise from the fact that both patients were asymptomatic and both showed unexpected echocardiographic findings. Asymptomatic presentation is very rare, and occurs in only about 10% of individuals. Atrial myxomas discovered on incidental echocardiography is also a rare phenomenon, as seen in our cases. Early diagnosis and timely surgical treatment allow these patients to live a completely asymptomatic life.

Redefining Cut-Points for High Symptom Burden of the Global Initiative for Chronic Obstructive Lung Disease Classification in 18,577 Patients With Chronic Obstructive Pulmonary Disease.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) can be classified into groups A/C or B/D based on symptom intensity. Different threshold values for symptom questionnaires can result in misclassification and, in turn, different treatment recommendations. The primary aim was to find the best fitting cut-points for Global initiative for chronic Obstructive Lung Disease (GOLD) symptom measures, with an modified Medical Research Council dyspnea grade of 2 or higher as point of reference. METHODS: After a computerized search, data from 41 cohorts and whose authors agreed to provide data were pooled. COPD studies were eligible for analyses if they included, at least age, sex, postbronchodilator spirometry, modified Medical Research Council, and COPD Assessment Test (CAT) total scores. MAIN OUTCOMES: Receiver operating characteristic curves and the Youden index were used to determine the best calibration threshold for CAT, COPD Clinical Questionnaire, and St. Georges Respiratory Questionnaire total scores. Following, GOLD A/B/C/D frequencies were calculated based on current cut-points and the newly derived cut-points. FINDINGS: A total of 18,577 patients with COPD [72.0% male; mean age: 66.3 years (standard deviation 9.6)] were analyzed. Most patients had a moderate or severe degree of airflow limitation (GOLD spirometric grade 1, 10.9%; grade 2, 46.6%; grade 3, 32.4%; and grade 4, 10.3%). The best calibration threshold for CAT total score was 18 points, for COPD Clinical Questionnaire total score 1.9 points, and for St. Georges Respiratory Questionnaire total score 46.0 points. CONCLUSIONS: The application of these new cut-points would reclassify about one-third of the patients with COPD and, thus, would impact on individual disease management. Further validation in prospective studies of these new values are needed.

Dilemma in clinical diagnosis of right ventricular masses.

Detection of an intracardiac mass always represents a clinical challenge. We present a 61-year-old female patient with symptoms of New York Heart Association class III. Two-dimensional transthoracic echocardiography revealed a hypoechogenic mass in the cavity of the dilated right ventricle (RV). Cardiac MRI described a pathologic structure of the RV free wall with pedunculated tumor in its cavity. Three months later, on a repeated echocardiography, there were three individual masses. The patient underwent surgery and the pathohistologic report demonstrated thrombotic masses. During the postoperative period, after reviewing all medical records, the conclusion was arrhythmogenic RV cardiomyopathy. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:362-369, 2017.

The Role of Tonsillectomy in the Prevention of Helicobacter Pylori Infection.

The incidence of Helicobacter pylori infection varies globally and depends on the socioeconomic situation of a location. In the territory of Croatia, the incidence rate among the populace is 40-50% in persons with normal gastroscopic findings, whereas it is increased in persons with the pathohistological finding of the ulcus disease. This study examines the potential preventive role of tonsillectomy with regard to H. pylori infection in later stages of life. The survey was conducted on a sample of 115 examinees (63 male, 52 female), aged between 19 and 86. The survey included examinees that underwent esophagogastroscopy at the Institute of Gastroenterology of the University Hospital Centre Osijek based on indication by a gastroenterology specialist. The survey has shown that of the total of 115 examinees, 28 of them had been tonsillectomised, and 87 had not been tonsillectomised. In the examinees who had not been subjected to tonsillectomy, positive H. pylori result was found in 63.2%, and 53.6% of those who had been tonsillectomised at a young age were positive to H.pylori. The results have shown that H. pylori infection was equally represented in all age groups, and the rate varies at 52.9-64.8%. Hence, the final conclusion was reached that tonsillectomy has no preventive role with regard to H.pylori infection.

Assessment of endothelial dysfunction by measuring von Willebrand factor and exhaled nitric oxide in patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a multisystemic disease, one of the leading causes of mortality and morbidity. The aim of this research is to assess the level of markers of endothelial dysfunction, vWf and the exhaled nitric oxide (NO) depending on the severity of COPD. The study included 100 subjects: 60 patients with COPD without adjoining cardiovascular comorbidity, and 40 patients as the controls. The subjects underwent a fractional exhaled nitric oxide test (FeNO), spirometric testing, and diffusing capacity of the lung for carbon monoxide test (DLCO), samples were taken of their vein blood to analyze the level of vWf (using the vWf:RCO method), C-reactive protein (CRP), fibrinogen, cholesterol, triglycerides as well as the acid base status. COPD patients then filled COPD assessment test (CAT test) and the modified dyspnea scale (mMRC). The results showed that in patient group that higher levels of vWf are associated with lower values of exhaled NO, which means that higher levels of vWf are associated with lower values of exhaled NO. By comparing the ill subjects from four groups (A, B, C and D), a difference was established between the level of vWf [F (3.56 = 0.24; p = 0.869], while, although statistically not significant, the highest level of exhaled NO was found in group A and the lowest in group D. The rise in the value of vWf is followed by the rise of fibrinogen values, which is another marker of endothelial dysfunction. The results of this research have shown that a systemic inflammation and hypoxia in the early stages of COPD, when no significant changes in the absolute values of FEV1 are present, stipulate the existence of endothelial dysfunction together with the clinically relevant differences in the levels of vWf and exhaled NO.

[Risk assessment for sleep apnea syndrome and excessive daytime sleepiness in patients with chronic obstructive pulmonary disease]. / Procjena rizika za sindrom apneje u spavanju i prekomjerne dnevne pospanosti u bolesnika oboljelih od kronicne opstruktivne pluíne bolesti.

AIM: The objective of this study was to examine the risk of sleep apnea syndrome in patients with chronic obstructive pulmonary disease (COPD) and to determine correlation with the associated cardiovascular comorbidity in these patients. Chronic and occasional sleep disturbances represent a problem for millions of people worldwide. COPD is a multisystem disease and the leading cause of mortality and morbidity in the world. It is estimated that it will be the third cause of death in the world by 2020. Poor quality of sleep in patients with COPD occurs as a result of reduced oxygen saturation, hypercapnia, and the use of auxiliary respiratory muscles. METHODS: The study included 47 patients with COPD, examined at the Department of Pulmonology, Clinical Department of Internal Medicine, Osijek University Hospital Center in 2011. The respondents answered questions from the Croatian version of the Snoring, Tired, Observed, Pressure (STOP) questionnaire, which examines the risk of sleep apnea syndrome, and the Epworth Sleepiness Scale, which examines excessive daytime sleepiness. The respondents also provided data related to the current smoking status, bronchodilation therapy they apply at home, the associated cardiovascular comorbidity related to coronary heart disease (previous myocardial infarction, angina pectoris), cerebrovascular incident, diabetes, asthma, gastroesophageal reflux disease (GERD) and anxiety-depressive disorder. RESULTS: According to the STOP questionnaire, the risk of sleep apnea syndrome was recorded in 35 (74.5%) respondents. Patients at risk had a higher frequency of comorbidities such as hypertension, diabetes mellitus type 2 and GERD. Excessive daytime sleepiness was recorded in 14.9% of patients with COPD and the mean daytime sleepiness scored 4.76 points. In patients at a high risk according to the STOP questionnaire, the mean daytime sleepiness was 6.24 points versus 3.72 points in the group at a low risk. Snoring was present in 23 (49%), excessive tiredness in 27 (57%), and cessation of breathing during sleep in every other person in 4 cases (8.5% of patients). The t-test showed no significant differences in oxygen saturation, partial O2 and CO2 pressures between the groups of non-risk and high-risk patients according to the STOP questionnaire. CONCLUSION: For assessing the risk of sleep apnea syndrome in patients with COPD, the STOP questionnaire as a screening method has a significant role. Because of the high risk of sleep apnea syndrome in patients with COPD and considering the high level of associated cardiovascular comorbidity, it is necessary to perform polysomnography in patients at risk for timely detection and treatment of the syndrome, thus preventing its harmful consequences, with special reference to reduction of mortality in this population.