Association of intestinal inflammation and permeability markers with clinical manifestations of Parkinson's disease.

INTRODUCTION: Intestinal inflammation and gut microbiota dysbiosis can stimulate degeneration of dopaminergic neurons and development of Parkinson's disease (PD) via the gut-brain axis in certain patients. METHODS: In a case-control study, fecal markers of intestinal inflammation and permeability were measured using the ELISA method in PD patients and healthy controls. Motor and nonmotor symptoms were assessed using the Movement Disorder Society (MDS) Unified PD Rating Scale, Hoehn & Yahr scale, MDS Non-Motor Symptom Scale, Scales for Outcomes in PD - Autonomic Dysfunction, PD Sleep Scale - 2, Montreal Cognitive Assessment, Beck Anxiety Inventory, and Beck Depression Inventory-II. A correlation was established between the intestinal inflammation and permeability markers and PD symptoms. RESULTS: Higher levels of beta-defensin 2, zonulin and lactoferrin were recorded in PD patients compared to controls. Calprotectin and secretory immunoglobulin A showed no significant differences. Regression analysis indicated the roles of beta-defensin 2 and lactoferrin in predicting PD likelihood. Calprotectin yielded positive correlations with disease duration, depression, motor fluctuations, and gastrointestinal symptoms; beta defensin 2 with thermoregulation; and secretory immunoglobulin A with depression. Secretory immunoglobulin A showed negative correlation with age and age at disease onset, while zonulin showed negative correlation with the MDS Unified PD Rating Scale total score. CONCLUSIONS: Fecal markers differed in PD patients compared to controls and correlated with age, disease duration, and some nonmotor symptoms. Future studies should identify the subgroups of PD patients that are likely to develop intestinal inflammation.

Influence of Age, Gender, Frailty, and Body Mass Index on Serum IL-17A Levels in Mature Type 2 Diabetic Patients.

BACKGROUND The cytokine IL-17A is emerging as a marker of chronic inflammation in cardio-metabolic conditions. This study aimed to identify relevant factors that in older primary care patients with type 2 diabetes (T2D) could influence serum IL-17A concentrations. The results have a potential to improve risk stratification and therapy options for these patients. MATERIAL AND METHODS The study was conducted during a period of 4 months, in 2020, in the south-eastern region of Croatia. Patients from primary health care, diagnosed with T2D (N=170, M: F 75: 95, ≥50 years old), were recruited at their visits. Those with malignant diseases, on chemotherapy or biological therapy, with amputated legs, or at hemodialysis, were excluded. The multinomial regression models were used to determine independent associations of the groups of variables, indicating sociodemographic and clinical characteristics of these patients, with increasing values (quartiles) of serum IL-17A. RESULTS The regression models indicated the frailty index and sex bias are the key modifying factors in associations of other variables with IL-17A serum values. CONCLUSIONS Sex bias and the existence of different frailty phenotypes could be the essential determining factors of the serum IL-17A levels in community-dwelling patients with T2D age 50 years and older. The results support the concept of T2D as a complex disorder.

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.

Real-World Study on Vedolizumab Serum Concentration, Efficacy, and Safety after the Transition from Intravenous to Subcutaneous Vedolizumab in Inflammatory Bowel Disease Patients: Single-Center Experience.

Little is known about how the change from intravenous to subcutaneous vedolizumab in a real-life setting in inflammatory bowel disease patients on stable maintenance therapy affects clinical outcomes. We compared the data on vedolizumab serum trough concentration, efficacy, and safety prior to and six months after the switch from intravenous to subcutaneous vedolizumab. In total, 24 patients, 13 with ulcerative colitis (UC) and 11 with Crohn's disease (CD), were included. Mean serum trough concentration of intravenous vedolizumab was significantly lower than mean serum trough concentration of subcutaneous vedolizumab (p = 0.002). There was no significant difference between C-reactive protein levels, fecal calprotectin levels or clinical scores (Harvey-Bradshaw index or Partial Mayo score) prior to transition to subcutaneous vedolizumab and after 6 months. In four (16.7%) patients, two CD and two UC, therapy was discontinued during the follow-up period with a median of 5 months (minimum-maximum: 4-6). In all patients, therapy was discontinued due to loss of response. In total, 13 adverse events were reported by 11 patients, and the most common adverse event was COVID-19. No serious adverse events were reported. In conclusion, subcutaneous vedolizumab has shown to be effective and safe in patients on previously established maintenance therapy with intravenous vedolizumab.

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.

Endocannabinoids, Anandamide and 2-Arachidonoylglycerol, as Prognostic Markers of Sepsis Outcome and Complications.

Background: One of the major challenges in improving sepsis care is early prediction of sepsis complications. The endocannabinoid system has been intensely studied in recent years; however, little is known about its role in sepsis in humans. This study aimed to assess the prognostic role of endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), as early predictors of mortality, invasive mechanical ventilation (IMV) requirement, and length of stay (LOS) in patients with sepsis. Materials and Methods: In total, 106 patients with confirmed sepsis were enrolled in this study. The patients were divided into groups according to mortality outcome (survival, N=53; nonsurvival, N=53), IMV requirement (IMV group, N=26; non-IMV group, N=80), and LOS (LOS <10 days, N=59; LOS ≥10 days, N=47). Patients' clinical status was assessed along with laboratory biomarkers as well as AEA and 2-AG concentration measurements early on admission to emergency units. AEA and 2-AG levels were measured by enzyme-linked immunosorbent assay (ELISA) using an ELISA processor, EtiMax 3000 (DiaSorin, Saluggia, Italy). The predictive value of AEA and 2-AG for the studied sepsis outcomes and complications was analyzed using univariate and multivariate analyses and receiver operating characteristic (ROC) curve analysis. Results: Two endocannabinoids showed no significant difference between survivors and nonsurvivors, although an AEA concentration <7.16 µg/L predicted mortality outcome with a sensitivity of 57% (95% confidence interval [CI] 42-71) and specificity of 80% (95% CI 66-91). AEA concentrations ≤17.84 µg/L predicted LOS ≥10 days with sensitivity of 98% (95% CI 89-100) and specificity of 34% (95% CI 22-47). When analyzing IMV requirement, levels of AEA and 2-AG were significantly lower within the IMV group compared with the non-IMV group (5.94 µg/L [2.04-9.44] and 6.70 µg/L [3.50-27.04], p=0.043, and 5.68 µg/L [2.30-8.60] and 9.58 µg/L [4.83-40.05], p=0.002, respectively). The 2-AG showed the best performance for IMV requirement prediction, with both sensitivity and specificity of 69% (p<0.001). Endocannabinoid AEA was an independent risk factor of LOS ≥10 days (odds ratio [OR] 23.59; 95% CI 3.03-183.83; p=0.003) and IMV requirement in sepsis (OR 0.79; 95% CI, 0.67-0.93; p=0.004). Conclusion: Low AEA concentration is a prognostic factor of hospital LOS longer than 10 days. Lower AEA and 2-AG concentrations obtained at the time of admission to the hospital are predictors of IMV requirement.

Serum levels of interleukin 17 and 22 in patients with systemic sclerosis: a single-center cross-sectional study.

Systemic sclerosis (SSc) is a chronic, autoimmune disease characterized by inflammation, vasculopathy, and fibrosis of the skin and internal organs. Immunological response in SSc is still poorly understood. Cytokines play a significant role in this process leading to vasculopathy and fibrosis. In this cross-sectional study, we aimed to investigate serum levels of Th-17-related cytokines, IL-17 and IL-22, and to determine their correlation to the clinical association in SSc patients. Serum IL-17 and IL-22 levels were examined in 42 SSc patients and 29 healthy individuals. Associations between serum IL-17 and IL-22 levels and the duration of the disease, the extent of skin fibrosis, capillaroscopic findings, and involvement of the internal organs were explored. Serum IL-17 levels were not different in SSc and the control group. Serum IL-22 levels were significantly elevated in SSc patients compared to healthy individuals (p = 0.04). A positive correlation was found between the IL-22 sera levels and interstitial lung disease (p = 0.007). These results suggest IL-22 as a potential biomarker in SSc-related interstitial lung disease.

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.

Is postoperative cognitive decline after cardiac surgery associated with plasma beta amyloid 1-42 levels?

BACKGROUND: Postoperative cognitive decline following cardiac surgery is one of the frequently reported complications affecting postoperative outcome, characterized by impairment of memory or concentration. The aetiology is considered multifactorial and the research conducted so far has presented contradictory results. The proposed mechanisms to explain the cognitive decline associated with cardiac surgery include the neurotoxic accumulation of ß-amyloid (Aß) proteins similar to Alzheimer's disease. The comparison of coronary artery bypass grafting procedures concerning postoperative cognitive decline and plasmatic Aß1-42 concentrations has not yet been conducted. METHODS: The research was designed as a controlled clinical study of patients with coronary artery disease undergoing surgical myocardial revascularization with or without the use of a cardiopulmonary bypass machine. All patients completed a battery of neuropsychological tests and plasmatic Aß1-42 concentrations were collected. RESULTS: The neuropsychological test results postoperatively were significantly worse in the cardiopulmonary bypass group and the patients had larger shifts in the Aß1-42 preoperative and postoperative values than the group in which off-pump coronary artery bypass was performed. CONCLUSIONS: The conducted research confirmed the earlier suspected association of plasmatic Aß1-42 concentration to postoperative cognitive decline and the results further showed that there were less changes and lower concentrations in the off-pump coronary artery bypass group, which correlated to less neurocognitive decline. There is a lot of clinical contribution acquired by this research, not only in everyday decision making and using amyloid proteins as biomarkers, but also in the development and application of non-pharmacological and pharmacological neuroprotective strategies.

Clustering Inflammatory Markers with Sociodemographic and Clinical Characteristics of Patients with Diabetes Type 2 Can Support Family Physicians' Clinical Reasoning by Reducing Patients' Complexity.

Diabetes mellitus type 2 (DM2) is a complex disease associated with chronic inflammation, end-organ damage, and multiple comorbidities. Initiatives are emerging for a more personalized approach in managing DM2 patients. We hypothesized that by clustering inflammatory markers with variables indicating the sociodemographic and clinical contexts of patients with DM2, we could gain insights into the hidden phenotypes and the underlying pathophysiological backgrounds thereof. We applied the k-means algorithm and a total of 30 variables in a group of 174 primary care (PC) patients with DM2 aged 50 years and above and of both genders. We included some emerging markers of inflammation, specifically, neutrophil-to-lymphocyte ratio (NLR) and the cytokines IL-17A and IL-37. Multiple regression models were used to assess associations of inflammatory markers with other variables. Overall, we observed that the cytokines were more variable than the marker NLR. The set of inflammatory markers was needed to indicate the capacity of patients in the clusters for inflammatory cell recruitment from the circulation to the tissues, and subsequently for the progression of end-organ damage and vascular complications. The hypothalamus-pituitary-thyroid hormonal axis, in addition to the cytokine IL-37, may have a suppressive, inflammation-regulatory role. These results can help PC physicians with their clinical reasoning by reducing the complexity of diabetic patients.

PERIODONTAL DISEASE IN DIFFERENT STAGES OF CHRONIC KIDNEY DISEASE.

Periodontal disease is a chronic multifactorial disease the worldwide incidence of which is higher than the incidence of caries and represents one of the leading problems in dental medicine. It is manifested by the loss of the attachment apparatus of the tooth and leads to the loss of teeth. Numerous studies have shown the association of periodontal disease and various chronic systemic diseases such as diabetes mellitus and cardiovascular disease. It is believed that low-grade level of chronic inflammation and release of bacterial toxins and inflammatory mediators in the bloodstream aggravate a chronic systemic disease. The purpose of our research was to investigate the possible association of periodontal disease and chronic kidney disease via the inflammatory cytokines path. In this cross-sectional study, we surveyed a total of 80 subjects divided into two groups. First group included subjects with chronic renal disease stages III and IV, and the second group included patients with chronic renal disease stage V that were on hemodialysis. We compared periodontal status, as well as serum levels of different cytokines, interleukin 6, interleukin 17A and tumor necrosis factor α between the two groups. The results showed no significant between-group differences in periodontal status, but interleukin 6 levels were significantly higher in the hemodialysis group of patients and were also associated with a poorer periodontal status.

Interleukin 17A and Toll-like Receptor 4 in Patients with Arterial Hypertension.

BACKGROUND/AIMS: Immune responses are involved in arterial hypertension. An observational cross-sectional case control study was conducted to estimate the association between Toll-like receptor 4 (TLR4) expression and interleukin (IL)-17A serum levels in patients with controlled and non-controlled hypertension. METHODS: We have enrolled 105 non-complicated otherwise healthy hypertensive patients: 53 with well-controlled blood pressure and 52 non-controlled. TLR4 peripheral monocytes expression and serum IL-17A levels were determined by flow cytometry and ELISA, respectively. RESULTS: Non-controlled patients exhibited higher TLR4 expression than well-controlled (25.60 vs. 21.99, P=0.011). TLR4 expression was lower in well-controlled patients who were prescribed beta blockers (18.9 vs. 22.6, P=0.005) and IL-17A concentration was higher in patients using diuretics in either group (1.41 vs. 2.01 pg/ml, P<0.001; well-controlled 1.3 vs. 1.8 pg/ml, P= 0.023; non-controlled 1.6 vs. 2.3 pg/ml, P=0.001). Correlation between IL-17A concentration and hypertension duration was observed in non-controlled patients (Spearman correlation coefficient . ρ=0.566, P<0.001) whereas in well-controlled patients a correlation was found between hypertension duration and TLR4 expression (ρ=0.322, P=0.020). CONCLUSIONS: Arterial hypertension stimulates the immune response regardless of blood pressure regulation status. Prolonged hypertension influences peripheral monocyte TLR4 expression and IL-17A serum levels. Anti-hypertensive drugs have different immunomodulatory effects: diuretics are associated with higher IL-17A concentration and beta-blockers with lower TLR4 expression.