Plasma Cytokeratin-18 Fragment Level Reflects the Metabolic Phenotype in Obesity.

There is growing interest in the non-invasive identification and monitoring of the outcome of liver damage in obese patients. Plasma cytokeratin-18 (CK-18) fragment levels correlate with the magnitude of hepatocyte apoptosis and have recently been proposed to independently predict the presence of non-alcoholic steatohepatitis (NASH). The aim of the study was to analyze the associations of CK-18 with obesity and related complications: insulin resistance, impaired lipid metabolism and the secretion of hepatokines, adipokines and pro-inflammatory cytokines. The study involved 151 overweight and obese patients (BMI 25-40), without diabetes, dyslipidemia or apparent liver disease. Liver function was assessed based on alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) and the fatty liver index (FLI). CK-18 M30 plasma levels, FGF-21, FGF-19 and cytokines were determined by ELISA. CK-18 values >150 U/l were accompanied by high ALT, GGT and FLI, insulin resistance, postprandial hypertriglyceridemia, elevated FGF-21 and MCP-1 and decreased adiponectin. ALT activity was the strongest independent factor influencing high CK-18 plasma levels, even after an adjustment for age, sex and BMI [ß coefficient (95%CI): 0.40 (0.19-0.61)]. In conclusion, the applied CK-18 cut-off point at 150 U/l allows to distinguish between two metabolic phenotypes in obesity.

Enhanced GIP Secretion in Obesity Is Associated with Biochemical Alteration and miRNA Contribution to the Development of Liver Steatosis.

Nutrient excess enhances glucose-dependent insulinotropic polypeptide (GIP) secretion, which may in turn contribute to the development of liver steatosis. We hypothesized that elevated GIP levels in obesity may affect markers of liver injury through microRNAs. The study involved 128 subjects (body mass index (BMI) 25-40). Fasting and postprandial GIP, glucose, insulin, and lipids, as well as fasting alanine aminotransferase (ALT), γ-glutamyltransferase (GGT), cytokeratin-18, fibroblast growth factor (FGF)-19, and FGF-21 were determined. TaqMan low density array was used for quantitative analysis of blood microRNAs. Fasting GIP was associated with ALT [ß = 0.16 (confidence interval (CI): 0.01-0.32)], triglycerides [ß = 0.21 (95% CI: 0.06-0.36], and FGF-21 [ß = 0.20 (95%CI: 0.03-0.37)]; and postprandial GIP with GGT [ß = 0.17 (95%CI: 0.03-0.32)]. The odds ratio for elevated fatty liver index (>73%) was 2.42 (95%CI: 1.02-5.72) for high GIP versus low GIP patients. The miRNAs profile related to a high GIP plasma level included upregulated miR-136-5p, miR-320a, miR-483-5p, miR-520d-5p, miR-520b, miR-30e-3p, and miR-571. Analysis of the interactions of these microRNAs with gene expression pathways suggests their potential contribution to the regulation of the activity of genes associated with insulin resistance, fatty acids metabolism, and adipocytokines signaling. Exaggerated fasting and postprandial secretion of GIP in obesity are associated with elevated liver damage markers as well as FGF-21 plasma levels. Differentially expressed microRNAs suggest additional, epigenetic factors contributing to the gut-liver cross-talk.

Effect of insulin resistance on whole blood mRNA and microRNA expression affecting bone turnover.

OBJECTIVE: To evaluate the effect of insulin resistance in obesity on the expression in whole blood of mRNA and miRNA affecting bone homeostasis as well as to estimate the influence of oral glucose load (OGTT) on serum osteocalcin concentration in obese individuals with and without insulin resistance. DESIGN: Cross-sectional study. METHODS: Carboxylated (cOC), undercarboxylated (ucOC) and total osteocalcin were measured by ELISA in the serum of obese subjects with insulin resistance (n = 41) and obese subjects without insulin resistance (n = 41) (control group) during OGTT. Analysis of gene expression (microarray) and miRNAs (real-time PCR) was performed in venous blood (representating samples) collected before OGTT from obese with insulin resistance and controls. RESULTS: Obese subjects with insulin resistance (higher HOMA-IR and lower oral glucose insulin sensitivity index) presented significantly increased expression of WNT signalling inhibitors (DKK1, DKK2, SOST, SFRP1) and downregulation of the key factor in WNT signalling - ß catenin participating in osteoblasts differentiation. Expression of miRNA involved in osteoblastogenesis was also inhibited (miR-29b, miR-181a, miR-210, miR-324-3p). During OGTT, contrary to the control group, subjects with insulin resistance presented suppression of cOC and total OC decrease after 1 and 2 h of oral glucose load. CONCLUSIONS: Obese subjects with insulin resistance may have defects in osteoblastogenesis that was demonstrated via key signalling molecules mRNA downregulation, and increased expression of WNT antagonists as well as inhibition of expression of miRNA participating in the regulation of osteoblast differentiation. Disturbed osteoblastogenesis in insulin-resistant subjects results in the suppression of blood carboxylated and total osteocalcin decrease during OGTT.

High Fat Mixed Meal Tolerance Test Leads to Suppression of Osteocalcin Decrease in Obese Insulin Resistant Subjects Compared to Healthy Adults.

Nutrients influence bone turnover. Carboxylated osteocalcin (Gla-OC) participates in bone formation whereas its undercarboxylated form (Glu-OC) acts as a hormone in glucose metabolism. The aim of the study was to determine the responses of Gla-OC, Glu-OC, and total-OC (calculated as the sum of Gla-OC and Glu-OC) to a high fat mixed meal tolerance test (HFMTT) in non-obese (body mass index (BMI) < 30 kg/m², n = 24) and obese subjects (30 < BMI < 40 kg/m², n = 70) (both sexes, aged 25⁻65 years). Serum Gla-OC and Glu-OC were measured at baseline as well as at 2 and 6 h during a HFMTT by enzyme-linked immunosorbent assay (ELISA). Baseline Gla-OC, Glu-OC, and total-OC levels were lower in obese individuals compared to non-obese participants (p = 0.037, p = 0.016 and p = 0.005, respectively). The decrease in Gla-OC and total-OC, but not in Glu-OC, concentrations during the HFMTT was suppressed in obese, but not in non-obese controls (p < 0.05, p < 0.01, p = 0.08, respectively). Subjects with the highest homeostatic model assessment for insulin resistance (HOMA-IR) index values had a less pronounced decrease in total-OC compared to patients with values of HOMA-IR index in the 1st quartile (p < 0.05). Net incremental area under Gla-OC inversely correlated with adiponectin (rho = -0.35, p = 0.001). Increase in insulin sensitivity and adiponectin level in obese subjects could beneficially influence postprandial bone turnover expressed by osteocalcin concentration.

Relation of the protein glycation, oxidation and nitration to the osteocalcin level in obese subjects.

Carboxylated osteocalcin (Gla-OC) contributes to the bone formation, whereas its undercarboxylated form (Glu-OC) takes part in the energy metabolism. In vitro studies had shown that treatment of osteoblast-like cells with advanced glycation end product-modified bovine serum resulted in reduced synthesis of collagen 1 and osteocalcin. The aim of this study was to find association between Gla-OC and markers of protein glycation, oxidation and nitration, as well as pro-inflammatory and antioxidant defense markers in obese subjects. Non-obese [(body mass index (BMI)<30 kg/m; n=34)] and obese subjects (30

Carboxylated and undercarboxylated osteocalcin in metabolic complications of human obesity and prediabetes.

BACKGROUND: Carboxylated osteocalcin (Gla-OC) participates in bone remodeling, whereas the undercarboxylated form (Glu-OC) takes part in energy metabolism. This study was undertaken to compare the blood levels of Glu-OC and Gla-OC in nonobese, healthy obese, and prediabetic volunteers and correlate it with the metabolic markers of insulin resistance and early markers of inflammation. METHODS: Nonobese (body mass index [BMI] <30 kg/m2 ; n = 34) and obese subjects (30

Dicarbonyl stress in clinical obesity.

The glyoxalase system in the cytoplasm of cells provides the primary defence against glycation by methylglyoxal catalysing its metabolism to D-lactate. Methylglyoxal is the precursor of the major quantitative advanced glycation endproducts in physiological systems - arginine-derived hydroimidazolones and deoxyguanosine-derived imidazopurinones. Glyoxalase 1 of the glyoxalase system was linked to anthropometric measurements of obesity in human subjects and to body weight in strains of mice. Recent conference reports described increased weight gain on high fat diet-fed mouse with lifelong deficiency of glyoxalase 1 deficiency, compared to wild-type controls, and decreased weight gain in glyoxalase 1-overexpressing transgenic mice, suggesting a functional role of glyoxalase 1 and dicarbonyl stress in obesity. Increased methylglyoxal, dicarbonyl stress, in white adipose tissue and liver may be a mediator of obesity and insulin resistance and thereby a risk factor for development of type 2 diabetes and non-alcoholic fatty liver disease. Increased methylglyoxal formation from glyceroneogenesis on adipose tissue and liver and decreased glyoxalase 1 activity in obesity likely drives dicarbonyl stress in white adipose tissue increasing the dicarbonyl proteome and related dysfunction. The clinical significance will likely emerge from on-going clinical evaluation of inducers of glyoxalase 1 expression in overweight and obese subjects. Increased transcapillary escape rate of albumin and increased total body interstitial fluid volume in obesity likely makes levels of glycation of plasma protein unreliable indicators of glycation status in obesity as there is a shift of albumin dwell time from plasma to interstitial fluid, which decreases overall glycation for a given glycemic exposure.

The diurnal profile of melatonin during delirium in elderly patients--preliminary results.

Delirium is an acute-onset syndrome that exacerbates patients' condition and significantly increases consequential morbidity and mortality. There is no comprehensive, cellular and tissue-level, pathophysiological theory. The melatonin hormone imbalance has been shown to be linked to circadian rhythms, sleep-wake cycle disturbances, and delirium incidence. There has been relatively little research about melatonin in delirium, and there has been no such study done in the group of elderly patients of a general medicine ward yet. The aim of our study was to compare melatonin hormone concentration in relation to the presence of delirium in elderly patients hospitalized in the general medicine ward. Blood samples were collected four times a day for two days (at 12:00, 18:00, 00:00 and 6:00), on the day when delirium was diagnosed and 72 h after the delirium resolution. Delirium was diagnosed with the Confusion Assessment Method and the criteria of the Diagnostic and Statistic Manual of Mental Disorders, 4th Revision. The mean age of 30 patients (73.3% women) was 86.5 ± 5.2 years. Delirium was diagnosed most often on the second and third day of hospitalization. A lot of predisposing and precipitating factors for delirium were identified. There was a significant difference in the melatonin hormone concentration measurement at 12:00 when patients had acute delirium and after its resolution [18.5 (13.8, 27.5) vs 12.9 (9.8, 17.8), p<0.01]. Different patterns of the melatonin hormone concentration were shown in analyses in the subgroups defined according to the patients' diagnosis of dementia. We found that the delirium recovery was, in fact, associated with the alteration of the daily profile of melatonin.

Effect of caloric restriction with or without n-3 polyunsaturated fatty acids on insulin sensitivity in obese subjects: A randomized placebo controlled trial.

BACKGROUND: Caloric restriction and n-3 polyunsaturated fatty acid (PUFA) supplementation protect from some of the metabolic complications. The aim of this study was to assess the influence of a low calorie diet with or without n-3 PUFA supplementation on glucose dependent insulinotropic polypeptide (GIP) output and insulin sensitivity markers in obese subjects. METHODS: Obese, non-diabetic subjects (BMI 30-40 kg/m(2)) and aged 25-65 yr. were put on low calorie diet (1200-1500 kcal/day) supplemented with either 1.8 g/day n-3 PUFA (DHA/EPA, 5:1) (n = 24) or placebo capsules (n = 24) for three months in a randomized placebo controlled trial. Insulin resistance markers and GIP levels were analysed from samples obtained at fasting and during an oral glucose tolerance test (OGTT). RESULTS: Caloric restriction with n-3 PUFA led to a decrease of insulin resistance index (HOMA-IR) and a significant reduction of insulin output as well as decreased GIP secretion during the OGTT. These effects were not seen with caloric restriction alone. Changes in GIP output were inversely associated with changes in red blood cell EPA content whereas fasting GIP level positively correlated with HOMA-IR index. Blood triglyceride level was lowered by caloric restriction with a greater effect when n-3 PUFA were included and correlated positively with fasting GIP level. CONCLUSIONS: Three months of caloric restriction with DHA + EPA supplementation exerts beneficial effects on insulin resistance, GIP and triglycerides. GENERAL SIGNIFICANCE: Combining caloric restriction and n-3 PUFA improves insulin sensitivity, which may be related to a decrease of GIP levels.

Metabolic complications and selected cytokines in HIV-infected individuals.

INTRODUCTION: Human immunodeficiency virus (HIV)-infected individuals are at a higher risk of developing metabolic disturbances. The pathogenesis of these complications is complex and not fully explored. OBJECTIVES: The aim of the study was to investigate the effect of HIV infection and antiretroviral (ARV) therapy on the development of metabolic changes and adipocytokine concentrations. The analysis of the differences in the investigated parameters among lipodystrophic and nonlipodystrophic patients was also performed. PATIENTS AND METHODS: A total of 42 HIV­infected patients on ARV therapy (HIV[+]ARV[+]), 13 HIV­infected ARV naive patients (HIV[+]ARV[-]), and 20 healthy controls were included in the study. A lipid profile, fasting free fatty acids (FFAs), glucose, insulin, and insulin resistance (homeostasis model assessment of insulin resistance--HOMA­IR) were tested. Serum concentrations of tumor necrosis factor α (TNF­α), interleukin 6 (IL­6), adiponectin, leptin, and fatty acid-binding protein 4 (FABP4) were determined. RESULTS: Increased FFA levels were observed in HIV(+)ARV(-) patients. HIV(+)ARV(+) patients had significantly higher triglycerides and insulin level compared with controls. HOMA­IR showed a tendency to be higher in HIV(+)ARV(+) patients compared with the other study groups. The ARV therapy longer than 2 years resulted in more pronounced metabolic abnormalities. HIV infection itself had a significant effect on inflammation expressed by elevated TNF­α and IL­6 levels. We did not observe differences in adiponectin and FABP4 concentrations among the study groups, while the leptin concentration was significantly lower in HIV­infected lipodystrophic than in nonlipodystrophic patients. CONCLUSIONS: HIV infection induces lipid disorders, especially associated with fatty acid turnover augmented by ARV therapy. Compared with FABP4, leptin is a better biological marker of metabolic complications in HIV­infected patients.

Mitochondrial function and apoptosis of peripheral mononuclear cells (PBMCs) in the HIV infected patients.

HIV infection results in the development of immunodeficiency mainly due to the apoptosis of infected and by stander CD4 cells. The aim of the study was to follow the mitochondrial dependent pathway of apoptosis, one of the suggested mechanisms of above process. The inner mitochondrial membrane potential (MMP), Adenosine-5'-triphosphate (ATP) generation, apoptosis and necrosis markers of peripheral mononuclear cells (PBMCs) were compared in HIV infected patients and HIV negative control group. The correlation of blood viral load, TNFα concentration, CD4 cells count and duration of ARV therapy was considered. Additionally, group of HIV infected ARV-naive patients was involved for the follow-up study and the effects of one year of ARV therapy on measured parameters were studied. PBMCs of HIV infected individuals (especially without ARV therapy) demonstrated lower MMP and ATP generation and higher percentage of apoptotic/necrotic PBMCs. Correlation between blood TNFα level and mitochondrial dysfunction was observed. The first months of ARV therapy resulted in most significant restoration of mitochondrial function and living PBMCs count. HIV infection and ARV therapy have significant impact on mitochondrial function and apoptosis of PBMCs. They are driven by abnormal mitochondrial function apoptosis of immune cells which seems to be the key element leading to immunosuppression, thus an early intervention in this process by therapy can be beneficial for symptomatology of HIV infected patients.

Peripheral blood concentrations of TGFß1, IGF-1 and bFGF and remodelling of the left ventricle and blood vessels in hypertensive patients.

BACKGROUND: Remodelling process is associated with activity of such substances as transforming growth factor ß1 (TGFß1), basic fibroblast growth factor (bFGF, FGF2), or insulin like growth factor-1 (IGF-1). In the course of hypertension the remodelling of blood vessels and heart muscle takes place. Studies performed on animal models as well as clinical trials on aetiology of left ventricular hypertrophy (LVH), documented elevated level of both mRNA and proteins of TGFß1 and IGF-1. AIM: To analyse the correlation between cytokine levels and vascular and LV remodelling. METHODS: One hundred seven patients with essential hypertension (age 50 ± 10 years) as well as 50 healthy volunteers participated in the study. Blood pressure was measured in the doctor's office as well as using the ABPM method. The LVH was diagnosed by echocardiographic examination, while ultrasound diagnostic was used to analyse the blood vessels remodelling measured as carotid intima-media thickness. Based on echocardiography results hypertensive patients were divided into two groups - with or without LVH. Peripheral blood concentration of analysed cytokines was measured using Enzyme-Linked Immunosorbent Assay (ELISA). The results were compared with data obtained from control group of normotensive participants. RESULTS: Values of single measurements of growth factors levels did not show significant differences between analysed groups (p = 0.322), and they did not correlate with the blood pressure levels. The tendency to negative correlation between parameters of diastolic LV function and plasma concentrations of IGF-1 and TGF was found. The value of IMT also did not show significant correlation with TGFß1, bFGF and IGF-1 in all investigated groups. CONCLUSIONS: The obtained results point to the limited usefulness of single measurements of TGFß1, bFGF as well as IGF-1 blood concentrations, as the potential prognostic factors of the remodelling of blood vessels and cardiac muscle in patients with essential hypertension.

Evaluation of genetic predisposition to insulin resistance by nutrient-induced insulin output ratio (NIOR).

BACKGROUND: New tools to identify genotype-phenotype interactions need to be described and implemented. The aim of this study was to identify correlation between the risk originating from gene variation and diet-dependent development of insulin resistance. METHODS: Insulin output in terms of area under the curve after an oral glucose tolerance test (AUC Ins OGTT) and lipid tolerance tests (AUC Ins OLTT) were measured in 167 overweight/obese patients. Estimation of the 18 common gene polymorphisms for obesity risk and standard phenotyping were performed. RESULTS: Insulin output (AUC Ins OGTT) correlated strongly between both insulin treatments across the whole group. However, within the genotype sub-groups, correlation was lower or did not exist. Using a nutrient-induced insulin output ratio (NIOR), calculated as AUC Ins OLTT/AUC Ins OGTT, values ranged from 0.42 to 5.83 and correlated significantly with body mass index (BMI) and leptin, but not with age, gender, waist-to-hip ratio (WHR) and homeostasis model assessment of insulin resistance (HOMA-IR) or plasma adiponectin. High NIOR was found in a subgroup of carriers of rare allelic variants of genes characteristic for poorer tolerance to lipids in the diet. Low NIOR values were found within a sub-group with rare genetic variants regulating carbohydrate metabolism. Thus, the new insulin index NIOR may distinguish gene variant carriers into groups of glucose- or lipid-sensitive phenotypes. CONCLUSIONS: We suggest that the OLTT/OGTT insulin output ratio (NIOR) may be predictive for identifying individuals who are phenotypically susceptible to insulin resistance in response to high fat or carbohydrate in their habitual diet.

The relationships between activation of non-specific inflammatory process and malnutrition in patients on peritoneal dialysis.

Malnutrition is a frequent complication among patients on chronic peritoneal dialysis and early recognition of malnutrition can be a key factor in successful treatment. The aim of the study was to assess the nutritional status of patients on peritoneal dialysis and to search for the relationships between activation of non-specific inflammatory process and progression of malnutrition. The study group included 60 patients (age 50.4+/-14 years) on peritoneal dialysis for 17.6+/-20 months. Fourty-six patients completed the entire 24-month observation period. Nutritional status was assessed using SGA scale, anthropometric measures, bioimpendance, and several biochemical parameters. Inflammatory markers included: IL-6, TNFalpha, fibrinogen and CRP. Severe malnutrition was observed in the range between 8.4% (5 subjects, group C in SGA scale) to 11.7% (7 subjects, BMI <20 kg/m2) of patients. The nutritional status of the entire cohort was constant over 2 years of observation (based on SGA scale), although the mean albumin level decreased significantly after 24 months of observation (from 39.55+/-3.5 to 37.63+/-3.7 g/l; p<0.01). The mean concentrations of CRP (4.8 and 5.25 mg/l), IL-6 (3.45 and 6.8 pg/ml) and leptin (22.95 and 22.2 ng/ml) were above reference ranges both at the initial and final assessment. Moreover, the concentration of IL-6 significantly increased (p<0.001) after 24 months of observation. Patients treated with PD are frequently affected by malnutrition. Our results indicate a strong association between nutritional indices and markers of inflammation.

[Markers of inflammation and large artery compliance in patients with chronic renal failure]. / Czynniki prozapalne a podatnosc duzych naczyn tetniczych u chorych z przewlekla niewydolnoscia nerek.

UNLABELLED: Chronic inflammation is a widely accepted pathophysiologic factor of development and progression of atherosclerosis. One of the most important consequences of atherosclerosis is accelerated arterial stiffness. The impact of chronic inflammation on arterial stiffness was not analyzed up to now in patients with end-stage renal disease treated with peritoneal dialysis (PD). The aim of the study was to evaluate the possible relationship between aortic pulse wave velocity (AoPWV), considered useful tool of aortic stiffness assessment and blood pressure parameters, anthropometric characteristics, pro-inflammatory cytokines and acute phase reactants in patients treated with PD. MATERIAL AND METHOSA: The study was performed in the group of 43 patients (19 F 24 M) with ESRD, in the mean age of 50.6 +/- 13.4 years and on dialysis for the mean period of 21.9 +/- 20.7 months. Pulse wave velocity was assessed using two pressure transducers placed on common carotid and femoral artery, connected with automatic processor. In all patients Tumor Necrosis Factor alpha (TNF alpha), interleukin 6 (IL-6), C- reactive protein and fibrinogen were assayed as 'markers of inflammation'. Blood pressure was also measured in the standardized conditions. Mean AoPWV equaled 10.7 +/- 2.1 m/s. Significant correlations were found between AoPWV, age, body weight and BMI. AoPWV was associated with systolic blood pressure, mean arterial pressure and pulse pressure. RESULTS: Significant correlations between AoPWV and serum IL-6 were shown, whereas association with CRP was close to statistical significance (p= 0,053). Associations between AoPWV, age and systolic blood pressure were also confirmed by multiple regression analysis. CONCLUSION: Chronic, uremia-dependent inflammation may be one of the factors influencing aortic stiffness in patients treated with PD.

Changes in common carotid artery intima-media thickness over 1 year in patients on peritoneal dialysis.

BACKGROUND: Accelerated atherosclerosis and vascular calcifications increase cardiovascular morbidity and mortality in patients on dialysis. Common carotid artery (CCA) intima-media thickness (IMT) is considered useful for imaging atherosclerosis non-invasively. Since chronic inflammation may accelerate atherosclerosis in end-stage renal disease patients, the aim of this 1 year study was to assess changes in CCA-IMT in stable peritoneal dialysis (PD) patients, and to search for possible associations between these changes and selected cytokines, acute phase proteins and other risk factors of atherosclerosis. METHODS: Of the original cohort of 61 stable patients on PD-28 female, 33 male; mean age 50.4+/-13.6 years; dialyse for a median of 17.5 months at inclusion (range 1-96 months)-47 patients survived the 1 year period on PD. CCA-IMT was assessed at baseline and after 12 months. Pro-inflammatory cytokines (IL-6, TNFalpha), acute phase proteins (CRP, fibrinogen), calcium-phosphate balance and lipid profile were assessed at baseline and after 6 and 12 months. Anthropometric parameters (age, weight, BMI, waist-to-hip ratio) were measured at baseline. RESULTS: The mean CCA-IMT at baseline, 0.66+/- 0.19 mm, increased by a mean of 0.098+/-0.17 to 0.76+/-0.21 mm (P<0.001) in 1 year. In 14 patients (29.8%) at least one plaque was found in the CCAs examined. At the end of follow-up: 28 patients (59.6%) had increases in CCA-IMT (from 0.63+/-0.2 to 0.83+/- 0.21 mm; P = 0.03), and 19 (40.4%) remained stable or even showed slight, but non-significant, decreases of CCA-IMT (from 0.72+/-0.17 to 0.66+/-0.17 mm, P = NS). The 'progressors' had significantly higher initial BMI (P<0.05), and mean concentrations of calcium (P = 0.005), IL-6 (P = 0.05), TNFalpha (P = 0.05), CRP (P = 0.005) and lower HDL-cholesterol than 'non-progressors'. In univariate analysis, DeltaCCA-IMT correlated positively with age (R = 0.32, P = 0.03), BMI (R = 0.29, P = 0.05) and mean concentrations of CRP (R = 0.37, P = 0.01), TNFalpha (0.52, P = 0.0002), but inversely with HDL-cholesterol (R = -0.37, P = 0.01). In multiple regression analysis, however, only age appeared to be independently associated with increase in CCA-IMT (beta = 0.37, P<0.01; R(2) for the model 0.14). CONCLUSIONS: Our results suggest a possible role of non-specific inflammation in the progression of atherosclerosis in patients treated with PD, in addition to age.

Trends and dynamics of changes in calcification score over the 1-year observation period in patients on peritoneal dialysis.

BACKGROUND: Accelerated vascular calcification is an important cause of excess mortality in patients on dialysis therapy. The aim of the study was to evaluate the trends in coronary artery calcification (CAC) score (CaSc) during a 1-year period in a group of stable peritoneal dialysis (PD) patients and identify factors that may be associated with CaSc changes. METHODS: Sixty-one stable patients (28 women, 33 men) on PD therapy with a mean age of 50.4 +/- 13.6 years were included. Forty-seven patients survived the entire study period on PD therapy and were suitable for the final analysis. CaSc was assessed at baseline and after 12 months by using multislice spiral computed tomography. Proinflammatory cytokines (interleukin-6, tumor necrosis factor-alpha [TNF-alpha]), acute-phase proteins (C-reactive protein [CRP], fibrinogen), calcium-phosphate balance, and lipid profile were assessed at baseline and after 6 and 12 months. RESULTS: Median CaSc was 22.6 Agatston units (range, 0 to 5,502.8 Agatston units) at baseline and increased to 84 Agatston units (range, 0 to 5,001.3 Agatston units) at a 1-year follow-up (P < 0.05). In the entire group of patients, 3 subgroups were identified: patients with progression (n = 21; P = 0.02 for the difference between initial versus follow-up CaSc), patients with regression (n = 12; P = 0.05), and subjects without change in CaSc after 1 year (n = 14). Patients without progression showed no calcifications at baseline and follow-up and were younger, less overweight, and characterized by significantly lower mean TNF-alpha, leptin, and CRP levels during 1 year compared with both progressors and regressors. Mean serum phosphate and calcium x phosphate product (Ca x P) values were gradually increasing from regressors through the no-calcification group to progressors (P < 0.01 for phosphate levels, P < 0.02 for Ca x P product). Significant correlations were found between changes in CaScs and mean values for phosphate (R = 0.44; P < 0.0005) and Ca x P product (R = 0.38; P < 0.005). CONCLUSION: Chronic nonspecific inflammation does not directly attribute to progression in CaScs. Calcium-phosphate balance abnormalities appear to be the only important factors promoting CAC, although a permissive or promoting role of inflammation cannot be ruled out.

The effect of hormone replacement therapy on endothelial function in postmenopausal women with hypertension.

BACKGROUND: Endothelial dysfunction has been implicated in the pathophysiology of cardiovascular diseases, including arterial hypertension. The present study was undertaken to assess endothelial function in postmenopausal women with arterial hypertension receiving hormone replacement therapy and antihypertensive treatment. MATERIAL/METHODS: A group of 76 women with natural menopause and essential mild to moderate arterial hypertension entered the study. Forty women received a transdermal, combined hormone replacement therapy (HRT) of 17 -estradiol and norethisterone acetate, whereas 36 served as controls. At baseline and at 3 and 12 months, all patients underwent 24-hr blood pressure monitoring and an exercise test, before which, at peak exercise, and after a 15-min recovery period venous blood was drawn to measure the level of nitrite/nitrate (NOx) according to the Griess RESULTS: At 3 and 12 months after beginning HRT, the level of NOx at rest was slightly increased, with marked individual differences in response to HRT. In women not receiving HRT, NOx did not change. In the HRT group, 52.5% at 3 months and 47.5% at 12 months had significantly increased levels compared with the baseline values (17.8+/-6.7 vs. 32.8+/-4.5 vs. 28.7+/-1.1 Kmol/l; p=0.002). The increased NOx level in responders was associated with decreased LDL cholesterol (3.62+/-1.2 vs. 3.53+/-1.3 vs. 2.6+/-0.6 mmol/l; p=0.01). At 12 months, blood pressure values did not differ from those at baseline in either group. CONCLUSIONS: The significant increase of NOx in half of the women receiving HRT suggests that only responders experience the cardioprotective effects of HRT.

Dexamethasone inhibits TNF-alpha synthesis more effectively in Alzheimer's disease patients than in healthy individuals.

Inflammatory mechanisms are involved in the pathogenesis of Alzheimer's disease (AD). It is postulated that cytokine synthesis is altered in AD patients compared with nondemented subjects. Glucocorticoids play an important role in cytokine synthesis. We assessed the release of tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10) and interleukin-12 (IL-12) and its regulation by dexamethasone in AD patients in vitro. Cytokine levels were measured using the ELISA method in unstimulated, LPS-stimulated or whole-blood samples incubated with LPS and dexamethasone from 18 AD patients and 12 controls. The cytokine levels spontaneously produced by blood cells after incubation with LPS or LPS and dexamethasone did not differ significantly between groups. Dexamathasone inhibited TNF-alpha synthesis by LPS-stimulated blood cells more effectively in AD patients than in controls. These results suggest that cytokine synthesis in AD patients could be regulated by glucocorticoids in a different way than in nondemented subjects.