Clinical effect of carotid stenting on cognitive abilities - possible evaluation using candidates for biomarkers.

Micro- and macrovascular consequences of atherosclerosis, arterial hypertension, dyslipidemia, and smoking can affect neurotransmission and markers for neuronal activity. The potential direction and specifics are under study. It is also known that optimal control of hypertension, diabetes, and dyslipidemia in midlife may positively affect cognitive functioning later in life. However, the role of hemodynamically significant carotid stenoses in neuronal activity markers and cognitive functioning is still being debated. With the increased use of interventional treatment for extracranial carotid disease, the question of whether it might affect neuronal activity indicators and whether we can stop or even reverse the path of cognitive deterioration in patients with hemodynamically severe carotid stenoses naturally emerges. The existing state of knowledge provides us with ambiguous answers. We sought the literature for possible markers of neuronal activity that can explain any potential difference in cognitive outcomes and guide us in the assessment of patients throughout carotid stenting. The combination of biochemical markers for neuronal activity with neuropsychological assessment and neuroimaging may be important from practical point of view and may provide the answer to the question for the consequences of carotid stenting for long-term cognitive prognosis.

Serum and Urinary Biomarkers in COVID-19 Patients with or without Baseline Chronic Kidney Disease.

In a prospective, observational, non-interventional, single-center study, we assessed various plasma and urinary biomarkers of kidney injury (neutrophil gelatinase-associated Lipocain [NGAL], kidney-injury molecule-1 [KIM-1], and interleukin-18 [IL-18]); inflammation (IL-6, C-reactive protein [CRP]); plus angiotensin converting enzyme 2 (ACE2) in 120 COVID-19 patients (of whom 70 had chronic kidney disease (CKD) at emergency-department (ED) admission). Our aim was to correlate the biomarkers with the outcomes (death, acute kidney injury [AKI]). All patients had received a chest-CT scan at admission to calculate the severity score (0-5). Biomarkers were also assessed in healthy volunteers and non-COVID-19-CKD patients. These biomarkers statistically differed across subgroups, i.e., they were significantly increased in COVID-19 patients, except for urinary (u)KIM1 and uIL-18. Amongst the biomarkers, only IL-6 was independently associated with mortality, along with AKI and not using remdesivir. Regarding the prediction of AKI, only IL-6 and uKIM1 were significantly elevated in patients presenting with AKI. However, AKI could not be predicted. Having high baseline IL-6 levels was associated with subsequent ventilation requirement and death. The mortality rate was almost 90% when the chest CT-scan severity score was 3 or 4 vs. 6.8% when the severity score was 0-2 (p < 0.0001).

Circulating Asprosin Concentrations in Patients with Obesity and Carbohydrate Disturbances.

Asprosin is a fasting-induced glucogenic hormone, secreted by white adipose tissue in response to starvation. The aim of the current study was to determine the levels of asprosin in subjects from the entire spectrum of the carbohydrate metabolism. A total of 153 Causcasian subjects participated in this study: group 1, healthy volunteers; group 2, obese subjects without glycemic disturbances; group 3, subjects with prediabetes and group 4, patients with newly identified type 2 diabetes. Subject with body mass index≥30 kg/m2 and dysglycemia (prediabetes and diabetes) showed significantly high levels of asprosin (1.40 ng/ml [IQR=0.98-1.94]; 1.27 ng/ml [IQR=0.86-2.12]; 1.09 ng/ml [IQR=0.89-1.58]) compared to the control group (0.71 ng/ml [IQR=0.54-0.92]; p<0.001). Correlation analysis showed that serum asprosin also had significant positive associations with some anthropometric parameters, liver enzymes, fasting and post load glucose and insulin, LDL and triglycerides. Furthermore, we estimated a marked relationship between asprosin concentrations and intima media thickness of the common carotid artery as well as neuropathy disability and vibration sensitivity. The circulating asprosin levels for differentiating subjects with carbohydrate disturbances and those with obesity were determined by ROC analysis. The AUC for disturbances of the glucose metabolism was 0.672 (p<0.001; 95% CI=0.581-0.751) and for obesity AUC was 0.849 (p<0.001; 95% CI=0.785-0.919). Circulating asprosin could be used as a predictive factor for early carbohydrate disorders and might be a potential new therapeutic target for the treatment of dysglycemia and obesity. Further prospective studies are needed to confirm this observation.

Neurotrophins in carotid atherosclerosis and stenting.

INTRODUCTION: Carotid stenting is used with an expanding indications. The neurotrophins are a family of proteins that induce the survival, development, and function of neurons. Carotid stenting alters cerebral blood flow and can affect neurotrophins' levels. MATERIAL AND METHODS: We included 78 people: 39 with significant carotid stenoses (CS) referred for carotid stenting (mean age 67.79 ± 10.53 years) and relatively healthy control group of 39 people without carotid and vertebral artery disease (mean age 57.42 ± 15.77 years). Brain derived reurotrophic factor (BDNF) and neuronal growth factor (NGF) concentrations were evaluated with ELISA method from venous blood - once for the control group; and for the carotid stenting group: before (n33), 24 h after (n22) and at least 1 month after (n18) carotid stenting. RESULTS: There was a difference between the mean neurotrophins' concentration of patients with significant carotid stenoses and the group without: BDNF p = 0.001, CI (-5.11 to -1.44) (3.10 ± 3.10 ng/ml in CS vs. 6.37 ± 4.67 ng/ml in controls); NGF p = 0.049, CI (0.64-347.75), 195.67 ± 495.34 pg/ml in CS vs. 21.48 ± 52.81 pg/ml in controls. BDNF levels before carotid stenting (3.10 ± 3.10 ng/ml) were significantly lower than the postprocedural (4.99 ± 2.57 ng/ml) - p < 0.0001, CI (-2.86 to -0.99). For NGF there was a tendency for lower values after stenting: 195.67 ± 495.34 pg/ml before vs. 94.92 ± 120.06 pg/ml after, but the result did not reach statistical significance. The neurotrophins levels one month after carotid stenting and controls' were not significantly different p < 0.01 (BDNF 5.03 ± 4.75 ng/ml vs. 6.37 ± 4.67 ng/min; NGF 47.89 ± 54.68 pg/ml vs. 21.48 pg/ml). DISCUSSION AND CONCLUSION: Periprocedural and mid-term concentrations of neurotrophins after carotid stenting change in non-linear model. This may be due to changes in cerebral perfusion and also might be involved in neuronal recovery and reparation after reperfusion.KEY MESSAGESPeriprocedural and mid-term concentrations of neurotrophins after carotid stenting change in non-linear model.As the majority of them are not specific, their periprocedural change can be used as a clinical correlate to guide changes or even success in carotid stenting.Changes in neutrophins' concentrations may be due to changes in cerebral perfusion and also might be involved in neuronal recovery and reparation after reperfusion.This goes in analogy with cardiac high-sensitive troponin, used as procedural guidance in coronary interventions.

Analysis of 2-Arachidonoylglycerol Levels in Polycystic Ovary Syndrome in the Context of Hormonal and Metabolic Alterations and Across the Classical Phenotypes.

Introduction: Ovarian folliculogenesis requires a fine balance between extra- and intra-ovarian factors. Endocannabinoids are found in the female reproductive system and are essential for a normal follicular growing process and ovulation. First, our study aimed to analyze levels of the endocannabinoid-2-arachidonoylglycerol (2-AG)-in patients with polycystic ovary syndrome (PCOS) and to compare with healthy controls. In addition, the study aimed to explore the association of 2-AG with hormonal and metabolic alterations, ovulatory dysfunction, and the presence of polycystic ovarian morphology (PCOM) across the classical PCOS phenotypes. Methods: Fifty-four women with PCOS were compared with 26 healthy controls. PCOS patients were diagnosed and phenotyped according to the Rotterdam criteria. Further analyses were performed with the classical PCOS phenotypes A and B comprising hyperandrogenism with oligo-anovulation with or without PCOM, respectively. Full medical history, clinical investigations, anthropometric measurements, laboratory tests, and ultrasound investigations were carried out in the follicular phase. Serum levels of 2-AG were measured by enzyme-linked immunosorbent assay. Results: PCOS patients (n=54) and healthy controls (n=26) showed similar metabolic parameters and anthropometric characteristics. PCOS patients were more hirsute than healthy women (p=0.001). Luteinizing hormone/follicle-stimulating hormone ratio and serum levels of androgens were significantly higher in the patient than in the control group (p=0.035, p<0.001, respectively). Free androgen index was also higher in the patient group (p=0.002). Serum levels of 2-AG did not significantly differ when comparing all PCOS patients versus healthy controls; however, further analysis of individual phenotype groups revealed that 2-AG levels in PCOS patients with phenotyope A (n=30) were significantly lower when compared with PCOS patients with phenotype B (n=20) and healthy controls (n=26). Conclusion: Serum levels of 2-AG were similar between PCOS patients and healthy controls. Nevertheless, phenotype A PCOS patients had significantly lower levels of the endocannabinoid compared with phenotype B patients and healthy controls. Collectively, these results suggest that overall serum levels of 2-AG are not a diagnostic marker for PCOS; however, their altered secretion or activity may influence normal follicular processes.

IL-6 and SAA-Strong Predictors for the Outcome in COVID-19 CKD Patients.

In this prospective study, we assessed biomarkers of inflammation (IL-6 and SAA) from the serum of 120 COVID-19 patients, of whom 70 had chronic kidney disease. All the samples were taken at emergency-department (ED) admission. Our goal was to relate the biomarkers to the results of death and acute kidney injury. All the patients underwent chest computer tomography to estimate the severity score (0-5), which was performed at hospital admission. Finally, biomarkers were also evaluated in a healthy control group and in non-COVID-19-CKD patients. IL-6 and SAA were statistically different between the subgroups, i.e., they were significantly increased in patients with COVID-19. Both of the biomarkers (IL-6 and SAA) were independently associated with mortality, AKI and a higher grade of pathological changes in the lung's parenchyma. Both high baseline levels of IL-6 and SAA on hospital admission were highly correlated with a later ventilatory requirement and mortality, independent of hospital stay. Mortality was found to be significantly higher when the chest CT severity score was 3-4, compared with a severity score of 0-2 (p < 0.0001). Conclusions: at the admission stage, IL-6 and SAA are useful markers for COVID-19 patients with CKD.

Frequency Distribution of CYP2C9 and VKORC1 Mutations among Bulgarian Patients and their Importance for Anticoagulant Therapy.

BACKGROUND: Genetic polymorphisms of CYP2C9 and VKORC1 play a major role in pharmacokinetics and pharmacodynamics of coumarin anticoagulants. The purpose of our study was to assess the relative frequency of the above mutations in Bulgarian population in order to predict bleeding tendencies and precisely manage the anticoagulant therapy during the postoperative period after cardiac surgery with extracorporeal circulation. METHODS: Genomic DNA samples from 200 Bulgarian patients subjected to cardiac surgery with extracorporeal circulation were analyzed for VKORC1 1639G>A and CYP2C9*2&*3 polymorphisms by real-time polymerase chain reaction (PCR), then allele frequencies of various genotypes were calculated by Hardy-Weinberg Equilibrium. RESULTS: Median patients' age was 63.9 ± 10.8 years; 66.5% were male. Median BMI was 28.6 ± 5.4 kg/m2. Genotype distribution for CYP2C9 was *1/*1 - 51%, *1/*2 - 21%, *1/*3 - 13.5%, *2/*3 - 4%, *3/*3 - 2%, and *2/*2 - 1.5%. The calculated frequency of CYP2C9*1 allele was 74.25%, CYP2C9*2 allele was 13%, and CYP2C9*3 allele was 12.75%, and all allelic frequencies were in Hardy-Weinberg equilibrium (p-value = 0.358). The major VKORC1 genotype was G/A - 47%, followed by G/G - 35.5% and A/A - 17.5%). Based on Hardy-Weinberg Equilibrium, there was no significant difference between observed and expected frequencies (X - -3.779), presumably as a result of the homogeneity in the population. CONCLUSIONS: Analysis of the data obtained in the course of the study suggested that identification of homozygous carriers of VKORC1-1639 G>A (rs9923231) in Bulgarians may be useful in developing recommendations for personalized therapy. On the contrary, homozygous carriers of CYP2C9*2 or *3, included only 4.5% of the studied patients, thus indicating that this group would benefit less from dosing algorithms. Our results demonstrated good agreement with the results obtained in other studies conducted in the Caucasian population.

IL-18 Serum Levels in Patients with Obesity, Prediabetes and Newly Diagnosed Type 2 Diabetes.

BACKGROUND: Obesity and diabetes are related to chronic low-grade inflammation. As a pro-inflammatory cytokine, IL-18 stimulates various cell types and has pleiotropic functions. OBJECTIVE: To assess the levels of IL-18 in subjects from the entire spectrum of glycemic disorders. METHODS: This study included 387 Caucasians divided into four groups: healthy controls, obese subjects without carbohydrate issues, prediabetic patients, and recently discovered type 2 diabetics. RESULTS: Subject with body mass index ≥30kg/m2 and glycemic disorders showed significantly high levels of IL-18 (249.77 ± 89.96 pg/ml; 259.01 ± 95.70 pg/ml; and 340.98 ± 127.65 pg/ml) compared with that of the control group (219.47 ± 110.53 pg/ml, p < 0.05). IL-18 also had significant positive associations with some anthropometric parameters, liver enzymes, fasting, post-load glucose, insulin, uric acid, and triglycerides while negative with HDL. The circulating IL-18 levels for differentiating subjects with carbohydrate disturbances and those with metabolic syndrome were determined by ROC analysis. The AUC for the disturbances of the carbohydrate metabolism was 0.597 (p = 0.001; 95% CI = 0.539 - 0.654) and for MS AUC was 0.581 (p = 0.021; 95 % CI = 0.516 - 0.647). CONCLUSION: Our data indicate that as the levels of IL-18 are increased the carbohydrate tolerance is deteriorated. However, the significance of IL-18 in the progression of diabetes mellitus and subsequent consequences requires further exploration.

Polycystic ovary syndrome and (pre)osteoarthritis: assessing the link between hyperandrogenism in young women and cartilage oligomeric matrix protein as a marker of cartilage breakdown.

INTRODUCTION: OBJECTIVES: Our aim was to analyze the link between hyperandrogenism and early clinical manifestations of osteoarthritis (OA), knee cartilage thickness, and serum cartilage oligomeric matrix protein (sCOMP) levels in patients with polycystic ovary syndrome (PCOS) and to compare them with healthy volunteers. METHODS: Fifty-four PCOS patients who met the Rotterdam criteria with phenotypes A, B, and C were included. They were compared with 26 age- and body mass index (BMI)-matched controls. Detailed anthropometric measurements and clinical evaluation for hyperandrogenism were performed for all participants who also filled in the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. Furthermore, laboratory tests including sCOMP and hormone quantification were performed in a fasting stage. Finally, an ultrasound assessment was carried out in randomly selected 56 study participants. RESULTS: PCOS women reported more prominent knee-related symptoms (p = 0.035) and more impaired activities of daily living (ADL) (p = 0.001) than controls. Cartilage thickness of the left and right medial condyle and left lateral condyle was significantly greater in PCOS group (n = 41) than in control group (n = 15) (p = 0.05, p = 0.006, and p = 0.036, respectively). COMP correlated significantly and negatively with testosterone levels (p = 0.029, r = - 0.297) in women with PCOS and the correlation remained significant after controlling for BMI. CONCLUSIONS: Women with PCOS may experience knee-related symptoms and impaired ADL. They had greater knee femoral cartilage thickness. Although sCOMP levels did not significantly differ between the groups, lower levels of sCOMP may be inherent to PCOS patients with higher testosterone levels. Key Points • Although PCOS patients may experience more prominent knee related symptoms, their femoral cartilage of the knee joint is found thicker than controls. • PCOS patients did not have significantly elevated levels of sCOMP. • Lower sCOMP levels were related to higher testosterone levels.

Biclonal myeloma in renal failure.

Multiple myeloma is a clonal proliferation of the plasma cell line that accounts for approximately 10% of all hematological malignancies. It is characterized by abnormal growth of plasma cells producing monoclonal immunoglobulin or light chain (paraprotein), with subsequent development of osteolytic bone lesions, anemia, hypercalcemia, and renal failure. In 3-6% of myeloma patients, more than one monoclonal protein (usually two) is discovered, with different heavy or light chain or both. These additional monoclonal proteins may be identified at the time of diagnosis or appear later during an observation or therapy. The authors describe two patients with biclonal myeloma, one diagnosed during evaluation for newly discovered renal failure, and one identified in the course of treatment of monoclonal gammopathy. The discussion of the diagnosis, natural history, and prognosis in patients with biclonal myeloma are also reported.

Fibroblast growth factor 23 and 25(OH)D levels are related to abdominal obesity and cardiovascular risk in patients with polycystic ovarian syndrome.

Fibroblast growth factor 23 (FGF23) and Klotho are extensively studied in relation to bone metabolism and progression of chronic kidney disease. There is very limited information about their role in polycystic ovarian syndrome (PCOS). The aim of the present study was to investigate some bone markers in women with PCOS in relation to obesity and cardiovascular risk. In the study were included 80 patients, divided into three age-matched groups -Non-obese PCOS (n = 40); Obese PCOS (n = 20) and Obese control group (n = 20). Bone marker levels were measured by an enzyme-linked immunosorbent assay. Obese PCOS patients had higher levels of FGF23 and sRANKL, lower levels of 25(OH)D and higher prevalence of vitamin D deficiency compared to non-obese subjects. Patients with abdominal obesity (waist circumference >80 cm) independently of PCOS status had significantly higher levels of FGF23 (112.5 ± 86.5 vs. 73.4 ± 37.9 pg/ml; p = .023) and lower of 25(OH)D (35.8 ± 21.4 vs 47.8 ± 26.5 nmol/l; p = .034). Patients with PCOS at risk of cardiovascular diseases according to AE-PCOS consensus also had increased levels of FGF23 (111.6 ± 84.5 vs. 66.5 ± 35.1 pg/ml; p = .031) and decreased levels of 25(OH)D (31.9 ± 16.8 vs. 47.1 vs 28.4 nmol/l; p = .017) compared to those not at risk. There was no correlation between bone markers and blood glucose levels, insulin resistance or hormonal levels.

Blood-Brain Barrier and Intrathecal Immune Response in patients with neuroinfections.

Cerebrospinal fluid/serum albumin ratio is one of the most informative parameters for blood-brain barrier (BBB) integrity in cases of central nervous system (CNS) infectious diseases. Normally, CNS albumin concentration is a function of diffusion processes along with CSF drainage and resorption. In pathological processes CSF albumin levels are dependent only on the rate of CSF drainage resulting in non-linear reciprocal changes of albumin quotient (Qalb). IgG, IgA and IgM concentrations both in CSF and serum can be compared to Qalb, thus determining the intrathecal immune response. The aim of the study was to detect BBB permeability impairment and the intrathecal immune response in patients with CNS infections with various etiologies. CSF/serum ratios were calculated and related to IgG IgA and IgM concentrations in CSF and blood serum. The results were integrated and presented by Reibergrams. The results demonstrated typical patterns which prove albumin to be the main modulator of protein dynamics and at the same time explicates the complex pathophysiological mechanisms involved in BBB disruption and intrathecal immune response in CNS infections. The diagnostic model presented in our study seeks to explain the observations of meningitis and meningoencephalitis pathophysiology and points out the mandatory cooperation between clinicians and laboratory for accurate diagnosis and proper treatment.