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Abstract High-density lipoprotein cholesterol (HDL-C) is not a homogenous lipid fraction, but it can be further divided into subfractions. It is well-known that the Roma population has a high prevalence of reduced HDL-C levels and cardiovascular diseases (CVDs). However, it is unknown how this reduction affects different HDL subfractions, and whether changes in their quantity/representation are associated with an increased cardiovascular risk among them. In the present study, the HDL subfraction profile of the Hungarian general (HG) and the Roma populations were compared, and the subfractions showing a significant difference between the two populations were identified. The association of HDL subfractions with CVD risk estimated by the Framingham risk score (FRS) and the Systematic COronary Risk Evaluation (SCORE) algorithms were also defined. The present study is the first to find a significant association between HDL subfractions and cardiovascular risk estimated by FRS and SCORE. Ten HDL subfractions were investigated on small but carefully selected samples comprising 100 control subjects (with normal lipid profile) and 277 case subjects (with reduced HDL-C levels) from HG and Roma populations of a complex health survey. The level of HDL-1 to 3 subfractions and HDL-L showed a significant inverse association with cardiovascular risk estimated by both SCORE and FRS algorithms, whereas HDL-4 to 6 and HDL-I only for FRS. A higher representation (in %) of HDL-1 to 3 has a significant risk-reducing effect, while HDL-8 to 10 has a risk-increasing effect estimated by FRS. Our results confirmed that reduced levels of HDL-6 and -7 expressed in mmol/L were significantly associated with Roma ethnicity.

Abstract Study objectives Obstructive sleep apnea hypopnea syndrome (OSAHS) is a sleep-related breathing disorder, characterized by excessive daytime sleepiness (EDS), paralleled by intermittent collapse of the upper airway. EDS may be the symptom of OSAHS per se but may also be due to the alteration of central circadian regulation. Irisin is a putative myokine and has been shown to induce BDNF expression in several sites of the brain. BDNF is a key factor regulating photic entrainment and consequent circadian alignment and adaptation to the environment. Therefore, we hypothesized that EDS accompanying OSAHS is reflected by alteration of irisin/BDNF axis. Methods Case history, routine laboratory parameters, serum irisin and BDNF levels, polysomnographic measures and Epworth Sleepiness Scale questionnaire (ESS) were performed in a cohort of OSAHS patients (n = 69). Simple and then multiple linear regression was used to evaluate data. Results We found that EDS reflected by the ESS is associated with higher serum irisin and BDNF levels; β: 1.53; CI: 0.35, 6.15; p = 0.012 and β: 0.014; CI: 0.0.005, 0.023; p = 0.02, respectively. Furthermore, influence of irisin and BDNF was significant even if the model accounted for their interaction (p = 0.006 for the terms serum irisin, serum BDNF and their interaction). Furthermore, a concentration-dependent effect of both serum irisin and BDNF was evidenced with respect to their influence on the ESS. Conclusions These results suggest that the irisin-BDNF axis influences subjective daytime sleepiness in OSAS patients reflected by the ESS. These results further imply the possible disruption of the circadian regulation in OSAHS. Future interventional studies are needed to confirm this observation.

Distress disorder (a collective term for generalized anxiety disorder and major depressive disorder) is a well-known co-morbidity of bronchial asthma. The irisin—brain-derived neurotrophic factor (BDNF) axis is a pathway that influences several neurobehavioral mechanisms involved in the pathogenesis of distress disorder. Thus, the aim of the present study was to quantify the serum irisin and BDNF concentrations in order to investigate the possible link between the irisin/BDNF axis and distress disorder in an asthma patient cohort. Data of 167 therapy-controlled asthma patients were analyzed. Demographic, anthropometric, and anamnestic data were collected, routine laboratory parameters supplemented with serum irisin and BDNF levels were determined, pulmonary function test was performed using whole-body plethysmography, and quality of life was quantified by means of the St. George's Respiratory Questionnaire (SGRQ). Correlation analysis as well as simple and multiple linear regression were used to assess the relationship between the irisin level and the Impacts score of SGRQ, which latter is indicative of the presence and severity of distress disorder. We have found a significant, positive linear relationship between the Impacts score and the reciprocal of irisin level. This association was stronger in patients whose BDNF level was higher, and it was weaker (and statistically non-significant) in patients whose BDNF level was lower. Our results indicate that higher serum irisin level together with higher serum BDNF level are associated with milder (or no) distress disorder. This finding suggests that alteration of the irisin/BDNF axis influences the presence and severity of distress disorder in asthma patients.

Background Pigment epithelium-derived factor (PEDF) is a serin protease inhibitor and a potent inhibitor of angiogenesis. Its serum level has significant associations with metabolic parameters. However, little is known about the association between PEDF levels and lipid parameters in renal transplanted (TX) patients. Therefore, our aim was to investigate the relationship between PEDF level and lipid parameters in TX patients.Methods Seventy TX patients (47 males, 23 females, mean age 51.7 ± 12.4 years) and 34 healthy controls were enrolled. We examined the serum creatinine, C-reactive protein, fasting glucose and lipid parameters right before, then 1 and 6 months after TX. High-density lipoprotein (HDL)-associated paraoxonase-1 (PON1) activities were measured spectrophotometrically. Lipoprotein subfractions were determined by Lipoprint. PEDF and oxidized low-density liporotein (oxLDL) levels were measured by ELISA.Results Before transplantation, patients had had a significantly higher PEDF level compared to control subjects (p

Background. As diabetes mellitus is a major risk factor of sepsis, we aimed to evaluate the possible effects of diabetes mellitus and poor glycemic control on the diagnosis of sepsis. Methods. In our retrospective study, we included diabetic, septic patients—in whom the diagnosis of sepsis was based on the systemic inflammatory response syndrome (SIRS) criteria (n = 112, SIRS group)—who had HbA1c levels measured either in the previous 30 days (n = 39, SIRS 30 d subgroup) or within 24 hours after their emergency department admission (n = 73, SIRS 24 h subgroup). We later selected those patients from the SIRS group, whose sequential organ failure assessment (SOFA) score was ≥2 (n = 55, SOFA group), and these patients were also divided based on the time of HbA1c measurement (n = 21, SOFA 30 d subgroup and n = 34, SOFA 24 h subgroup). We analyzed the relationship between laboratory parameters, length of hospital stay, and HbA1c. Results. We found a significant positive correlation between glucose and HbA1c (p

Background: Cardiovascular (CV) morbidity, mortality and metabolic syndrome are associated with rheumatoid arthritis (RA). A recent trial has suggested increased risk of major CV events (MACE) upon the Janus kinase (JAK) inhibitor tofacitinib compared with anti-tumor necrosis factor α (TNF-α) therapy. In our study, we evaluated lipids and other metabolic markers in relation to vascular function and clinical markers in RA patients undergoing one-year tofacitinib therapy. Patients and methods: Thirty RA patients treated with either 5 mg or 10 mg bid tofacitinib were included in a 12-month follow-up study. Various lipids, paraoxonase (PON1), myeloperoxidase (MPO), thrombospondin-1 (TSP-1) and adipokine levels, such as adiponectin, leptin, resistin, adipsin and chemerin were determined. In order to assess flow-mediated vasodilation (FMD), common carotid intima-media thickness (IMT) and arterial pulse-wave velocity (PWV) ultrasonography were performed. Assessments were carried out at baseline, and 6 and 12 months after initiating treatment. Results: One-year tofacitinib therapy significantly increased TC, HDL, LDL, APOA, APOB, leptin, adipsin and TSP-1, while significantly decreasing Lp(a), chemerin, PON1 and MPO levels. TG, lipid indices (TC/HDL and LDL/HDL), adiponectin and resistin showed no significant changes. Numerous associations were found between lipids, adipokines, clinical markers and IMT, FMD and PWV (p < 0.05). Regression analysis suggested, among others, association of BMI with CRP and PWV (p < 0.05). Adipokines variably correlated with age, BMI, CRP, CCP, FMD, IMT and PWV, while MPO, PON1 and TSP-1 variably correlated with age, disease duration, BMI, RF and PWV (p < 0.05). Conclusions: JAK inhibition by tofacitinib exerts balanced effects on lipids and other metabolic markers in RA. Various correlations may exist between metabolic, clinical parameters and vascular pathophysiology during tofacitinib treatment. Complex assessment of lipids, metabolic factors together with clinical parameters and vascular pathophysiology may be utilized in clinical practice to determine and monitor the CV status of patients in relation with clinical response to JAK inhibition.

Objectives Progranulin (PGRN) is a secreted growth factor that helps to regulate neuronal survival by blocking tumor necrosis factor-alpha (TNFα) receptors. The antioxidant alpha-lipoic acid (ALA) is used in diabetic neuropathy to improve nerve conduction and relieve neuropathic pain, but its effects on PGRN levels have not yet been elucidated. Methods In this prospective study, 54 patients with type 2 diabetes and peripheral neuropathy received 600 mg of ALA daily for 6 months. Twenty-four patients with diabetes without neuropathy were also included in the study. Serum PGRN and TNFα levels were determined using enzyme-linked immunosorbent assays. In addition, current perception threshold (CPT) testing was used to assess sensory neuropathy. Results After ALA treatment, serum PGRN levels were significantly increased and CPT values were significantly improved. Furthermore, there were significant positive correlations among TNFα, ICAM-1, and PGRN levels both before and after ALA treatment. A significant negative correlation was observed between the improvements in CPT and the PGRN levels. Furthermore, ICAM-1 levels were an independent predictor of PGRN levels. Conclusions Changes in serum PGRN levels indicate that ALA treatment may have beneficial effects on endothelial function and neuronal inflammation.

Background: Diabetic neuropathy (DN) is a very frequent microvascular complication of type 2 diabetes mellitus (T2DM). Obesity and physical inactivity are well-known risk factors for T2DM. Fibroblast growth factor 21 (FGF21) is a liver-secreted hormone with several beneficial effects on obesity-related metabolic disorders. We aimed to investigate the effect of short-term physical activity on the levels of FGF21, and its correlation with the severity of peripheral sensory polyneuropathy in T2DM patients. Methods: Thirty patients with DN were enrolled in the study, compared to age- and gender-matched controls. We conducted a six-week aerobic training program, which meant treadmill and cycle ergometers three times a week. Anthropometric and laboratory parameters were measured for each patient before and after intervention. Serum levels of FGF21, TNF-alpha, irisin, leptin and adiponectin were measured by ELISA. The sensory perception threshold (CPT) was quantitatively measured using Neurometer®. Results: We found significant decreases in BMI, waist circumference, HbA1c and TNF-alpha levels. From baseline to six-week follow-up, FGF21 levels were significantly increased in DN patients. Significant negative correlations were shown between the changes in FGF21 levels and BMI, between changes in FGF21 and the improvement of CPT values, and between the changes in FGF21 and TNF-alpha levels. There was no difference in irisin, adiponectin and leptin levels in DN patients after aerobic training program. Conclusions: The physical activity may increase the level of FGF21 in T2DM patients with neuropathy. Our results highlight the importance of regular physical activity in the treatment of diabetic neuropathy.

Background: Afamin is a liver-produced bioactive protein and features α- and γ-tocopherol binding sites. Afamin levels are elevated in metabolic syndrome and obesity and correlate well with components of metabolic syndrome. Afamin concentrations, correlations between afamin and vitamin E, afamin and lipoprotein subfractions in non-diabetic, obese patients have not been fully examined. Methods: Fifty non-diabetic, morbidly obese patients and thirty-two healthy, normal-weight individuals were involved in our study. The afamin concentrations were measured by ELISA. Lipoprotein subfractions were determined with gel electrophoresis. Gas chromatography–mass spectrometry was used to measure α- and γ tocopherol levels. Results: Afamin concentrations were significantly higher in the obese patients compared to the healthy control (70.4 ± 12.8 vs. 47.6 ± 8.5 μg/mL, p < 0.001). Positive correlations were found between afamin and fasting glucose, HbA1c, hsCRP, triglyceride, and oxidized LDL level, as well as the amount and ratio of small HDL subfractions. Negative correlations were observed between afamin and mean LDL size, as well as the amount and ratio of large HDL subfractions. After multiple regression analysis, HbA1c levels and small HDL turned out to be independent predictors of afamin. Conclusions: Afamin may be involved in the development of obesity-related oxidative stress via the development of insulin resistance and not by affecting α- and γ-tocopherol levels.

Abstract Background Obestatin is a ghrelin-associated peptide, derived from preproghrelin. Although many of its effects are unclear, accumulating evidence supports positive actions on both metabolism and cardiovascular function. To date, level of obestatin and its correlations to the lipid subfractions in non-diabetic obese (NDO) patients have not been investigated. Methods Fifty NDO patients (BMI: 41.96 ± 8.6 kg/m2) and thirty-two normal-weight, age- and gender-matched healthy controls (BMI: 24.16 ± 3.3 kg/m2) were enrolled into our study. Obestatin level was measured by ELISA. Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subfractions, intermediate density lipoprotein (IDL) and very low-density lipoprotein (VLDL) levels and mean LDL size were detected by nongradient polyacrylamide gel electrophoresis (Lipoprint). Results Serum level of obestatin was significantly lower in NDO patients compared to controls (3.01 ± 0.5 vs. 3.29 ± 0.6 μg/ml, p

Background: Cardiovascular (CV) morbidity, mortality, and metabolic syndrome are associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Here, lipids and other metabolic markers in relation to vascular function and clinical markers were evaluated in RA and AS patients undergoing one-year anti-TNF therapy. Patients and methods: Fifty-three patients including 36 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 17 AS patients treated with ETN were included in a 12-month follow-up study. Various lipids, paraoxonase (PON) and arylesterase (ARE) activities, myeloperoxidase (MPO) and adipokine levels were determined overtime. Ultrasonography was performed to determine flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT), and arterial pulse-wave velocity (PWV) in all patients. All assessments were performed at baseline and 6 and 12 months after treatment initiation. Results: Anti-TNF therapy decreased ARE activity, MPO, adiponectin, and chemerin levels after 12 months (p < 0.05). Lipids, PON activity, and leptin remained unchanged. Regression analyses suggested variable associations of IMT, PWV, and FMD with ARE, MPO, leptin, and lipids (p < 0.05). On the other hand, these metabolic parameters were significantly associated with disease duration, CV history, CRP, obesity, PWV, and IMT (p < 0.05). One-year anti-TNF treatment together with baseline leptin (p = 0.039) or CRP (p = 0.016) levels determined 12 months of lipid changes overtime. TNF inhibition together with baseline disease activity determined ARE activity changes (p = 0.046). Anti-TNF therapy and baseline chemerin levels determined IMT changes overtime (p = 0.003). Conclusions: Assessment of various metabolic parameters together with disease activity, CRP, and ultrasound-based techniques may exert additional value in determining CV burden and in monitoring the effects of biologics on preclinical vascular pathophysiology.

Background: Fetuin-A and retinol-binding protein 4 (RBP4) are secreted as both hepatokine and adipokine. These are involved in insulin resistance, obesity-related dyslipidemia, and atherosclerosis. To date, correlations of circulating fetuin-A and RBP4 with lipoprotein subfractions as well as high-density lipoprotein (HDL)-linked proteins have not been entirely investigated in morbid obese and lean non-diabetic subjects. Methods: One-hundred obese non-diabetic patients (body mass index, BMI: 42.5 ± 8.1 kg/m2) along with 32 gender and age-matched normal weight controls (BMI: 24.5 ± 2.5 kg/m2) were enrolled in our study. Serum fetuin-A and RBP4 were measured by ELISA. Lipoprotein subfractions were distributed by Lipoprint gelelectrophoresis. Results: Serum fetuin-A and RBP4 were unexpectedly lower in obese patients (p < 0.01 and p < 0.01, respectively) compared to controls and correlated with each other (r = 0.37; p < 0.001). Fetuin-A had positive correlations with HDL-C (r = 0.22; p = 0.02), apolipoprotein AI (apoAI) (r = 0.33; p < 0.001), very-low density lipoprotein (VLDL) subfraction (r = 0.18; p = 0.05), and large HDL subfraction levels (r = 0.3; p = 0.001) but did not show correlation with carbohydrate parameters in all subjects. RBP4 correlated positively with HDL-C (r = 0.2; p = 0.025), apoAI (r = 0.23; p = 0.01), VLDL subfraction (r = 0.37; p < 0.001), intermediate HDL subfraction (r = 0.23; p = 0.01), and small HDL subfraction (r = 0.21; p = 0.02) concentrations, as well as C-peptide levels in overall participants. Backward stepwise multiple regression analysis showed that serum fetuin-A concentration is best predicted by RBP4 and large HDL subfraction. In model 2, VLDL subfraction was the independent predictor of serum RBP4 level. Conclusions: Our data may indicate a potential role of fetuin-A and RBP4 in impaired lipoprotein metabolism associated with obesity.

Background. The elevated level of plasminogen activator inhibitor-1 (PAI-1) in obese subjects with metabolic syndrome and in patients with type 2 diabetes is well established. The association of plasma PAI-1 and lipid metabolism is still unclear. The aim of the present study was to determine the relationship between plasma PAI-1 levels and the distribution of lipoprotein subfractions in obese and lean nondiabetic individuals. Subjects and Methods. We enrolled fifty nondiabetic obese patients and thirty-two healthy volunteers. Lipoprotein subfractions were detected with Lipoprint System. Plasma PAI-1, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and myeloperoxidase (MPO) concentrations were determined with enzyme-linked immunosorbent assay (ELISA), while serum paraoxonase-1 (PON1) activities were measured by spectrophotometry. Results. The TNF-α, IL-6, oxidized low-density lipoprotein (oxLDL), and MPO levels were found to be significantly higher, while PON1 paraoxonase and arylesterase activities were nonsignificantly lower in the obese patients. Strong significant negative correlations were found between plasma PAI-1 concentration and mean LDL size, as well as between PAI-1 concentrations and the levels of the large and intermediate high-density lipoprotein (HDL) subfractions. In multiple regression analysis, PAI-1 was predicted by waist circumference and intermediate HDL subfraction. Conclusion. The significant correlations between PAI-1 levels and lipoprotein subfractions indicate the link between PAI-1 and lipid metabolism in obesity.

In the present study the signal transduction of the formyl-Met-Leu-Phe receptor was studied in granulocytes obtained from control subjects and patients with elevated low density lipoprotein levels. According to our results, 10 nm formyl-Met-Leu-Phe in control cells activates phospholipase C inducing a pronounced inositol phosphate production followed by a Ca2+ signal from intracellular pools. The pertussis toxin-sensitive O2- generation and leukotriene synthesis were moderate. In contrast, in granulocytes from hypercholesterolemic patients, formyl-Met-Leu-Phe triggered an intensive pertussis toxin-insensitive oxidative burst and leukotriene synthesis. The inositol trisphosphate and Ca2+ signals were decreased significantly in granulocytes of hypercholesterolemic patients and seem to be dependent on the extracellular Ca2+ content. Furthermore, in the resting granulocytes of hypercholesterolemic patients the [Ca2+]i and the membrane-bound protein kinase C activity were higher than in controls, the time of normalization after the low Ca2+ signal was delayed, while the membrane fluidity was decreased. Our results suggest that in these ex vivo experiments, the high level of circulating low density lipoprotein in patients can affect the membrane composition of granulocytes leading to altered signal transduction by the formyl-Met-Leu-Phe receptor, to altered Ca2+ pump-activity, and protein kinase C translocation.— Paragh, G., E. Kovács, I. Seres, T. Keresztes, Z. Balogh, J. Szabó, F. Teichmann, and G. Fóris. Altered signal pathway in granulocytes from patients with hypercholesterolemia. J. Lipid Res. 1999. 40: 1728–1733.