Janusz Solski

Citicoline Treatment Increases Retinal Dopamine Content in Rabbits

Citicoline (exogenous cytidine-5′-diphosphocholine) was reported to enhance dopaminergic neurotransmission in the brain. A few clinical studies showed beneficial effects of this drug on the function of the visual pathway in patients with glaucoma or amblyopia. The present study was aimed at determining whether citicoline could influence retinal catecholamine levels in adult male Albino rabbits. The animals received the drug (50 mg/kg i.p., twice daily) or vehicle for 7 days, and retinal catecholamine concentrations were determined by HPLC. Compared to vehicle-treated controls, citicoline-treated animals displayed a significantly higher retinal dopamine concentration and a tendency toward an increase in adrenaline concentration, while the noradrenaline concentration remained unchanged. It is, therefore, conceivable that citicoline reinforces dopaminergic transmission in the retina.

Serum fibroblast growth factor 21 is predictive of combined cardiovascular morbidity and mortality in patients with type 2 diabetes at a relatively short-term follow-up

AIMS We hypothesised that serum fibroblast growth factor 21 (FGF-21), a novel adipokine with postulated insulin-sensitizing effects, may be predictive of cardiovascular (CV) events in patients with type 2 diabetes (DM2) at a relatively short-term follow-up. METHODS Serum FGF-21 levels were assessed in 87 DM2 patients, aged 57-66 years, with the median duration of diabetes of 10 years, who were referred to the Department of Endocrinology for routine annual metabolic assessment. During a follow-up of 24 months, overall mortality, CV mortality and CV nonfatal events were registered. Cox proportional hazards regression assessed adjusted differences in CV morbidity and mortality risk. RESULTS Patients stratified according to serum FGF-21 levels ≤ and > the median value of 240.7 pg/mL showed no significant differences at baseline in gender distribution, diabetes duration, insulin therapy, BMI, biochemical profiles and previous CV events. At 24-month follow-up, 21 (24.1%) patients experienced a nonfatal CV event. A significantly (P=0.0013) higher incidence of the combined end point of CV morbidity and mortality was observed in the FGF-21>240.7 pg/mL group. In the multivariate Cox proportional hazards regression model, the presence of FGF-21>the median value was associated with a significant increase in the risk of the combined end point of CV morbidity and mortality (HR: 4.7, 95% CI 1.67-13.24). CONCLUSIONS The obtained results support the prognostic value of FGF-21 in DM2 and may provide a useful tool for stratification of CV prognosis in DM2 patients.

Concentration of Lp(a) and other Apolipoproteins in Predialysis, Hemodialysis, Chronic Ambulatory Peritoneal Dialysis and Post-Transplant Patients

Abstract Serum levels of lipids, lipoprotein(a) Lp(a) and other apolipoproteins were determined in 47 predialysis patients, 40 hemodialysis (HD) patients, 39 chronic ambulatory peritoneal dialysis (CAPD) patients, 11 patients after kidney transplantation and 47 healthy subjects as reference group. The predialysis, HD, and CAPD patients had disturbances in the concentration of serum triglyceride (TG), high density lipoprotein (HDL)-cholesterol, apolipoprotein AI (apoAI), total apoCIII, apoCIII present in the particles without apoB (apoCIII non B), and Lp(a) and HDL-cholesterol, low density lipoprotein (LDL)-cholesterol/HDL-cholesterol, HDL-cholesterol/apoAI, apoAI/apoB, and apoAI/apoCIII ratios. Predialysis patients had significantly lower concentrations of HDL-cholesterol and total apoE levels than CAPD patients and total apoE level than HD patients. Moreover, both HD and CAPD patients had significantly increased levels of apoB containing apoE (apoB:E) and apoB containing apoCIII (apoB:CIII). The concentrations of serum TG, total cholesterol, LDL-cholesterol, apoB, Lp(a) in CAPD patients were statistically higher than in HD patients. The patients after transplantation demonstrated normalization of lipid and lipoprotein parameters and lipoprotein ratios except serum levels of TG, total apoCIII, apoCIII non B and the apoAI/apoCIII ratio. We concluded that abnormal lipid and lipoprotein concentrations in patients with uremia may be the cause of their high risk of atherosclerosis, but post-transplant patients exhibited improved levels of serum lipids, Lp(a) and other lipoprotein parameters and lipoprotein composition, which could be an index of decreased atherogenic status.

ApoA- and apoB-containing lipoproteins and Lp(a) concentration in non-dialyzed patients with chronic renal failure.

Background: End-Stage renal disease is associated with accelerated atherosclerosis and a high incidence of cardiovascular disease. Methods: The serum levels of lipids and apolipoproteins and Lp(a) were determined in 51 patients with chronic renal failure (CRF) with various advancement, without interference of factors which might disturb Lp(a) metabolism and with proteinuria less than 0.5 g/24 h. The patients studied were divided into two groups: patients with moderate renal failure (CRF-M) and creatinine levels of 2–6 mg/dL n = 27; and predialysis patients with end stage renal disease (ESRD) and creatinine levels higher than 8.5 mg/dL n = 24. Results: In both studied groups serum concentrations of triglycerides (TG), total apoCIII, apoCIIInonB, apoB:CIII were statistically increased, (except total cholestrol (TC) and LDL-cholestrol (LDL-C), apoB, total apoE, apoEnonB, apoB:E), while the levels of HDL-cholestrol (HDL-C) and apoAI significantly decreased. Lipid and lipoprotein ratios as risk factors of atherosclerosis were similar in both groups. The TC/HDL-C ratio increased, while that of HDL-C/apoAI and apoAI/apoCIII decreased. Serum Lp(a) concentrations were significantly increased in both studied groups. The medians and ranges of Lp(a) concentration were similar in both groups. Serum Lp(a) levels correlated with total cholesterol (r = 0.295; p < 0.05), LDL-C (r = 0.312; p < 0.05) and apoB (r = 0.215; p < 0.05). In addition, no correlation was found between Lp(a) levels and albumin concentrations (r = 0.126; p = 0.421). Conclusion: Our results may indicate that the reduced levels of apoA-containing lipoproteins and increased TG-rich apoB-containing lipoproteins and Lp(a) indicated a clear atherogenic pattern in early renal disease. Increased Lp(a) concentration may result in nonspecific synthesis or catabolism disturbances. Measurement and monitoring of lipoprotein family profiles offers a new means for selecting appropriate therapies targeted for normalizing dyslipidemia in non-dialyzed patients.

Effect of parenteral cladribine on relapse rates in patients with relapsing forms of multiple sclerosis: results of a 2-year, double-blind, placebo-controlled, crossover study

Objective This randomized, 2-year, double-blind, placebo-controlled, crossover study evaluated cladribine for relapsing forms of multiple sclerosis. Design Patients (n = 84) received seven 5-day courses of subcutaneous cladribine at 5 mg/day (group A) or placebo (group B) in year 1; treatment was reversed in year 2. Results Cladribine was well tolerated and associated with a favorable safety profile. Mean Expanded Disability Status Scale scores remained stable. In group A, mean relapse rates were 0.15 in year 1 (cladribine) and 0.42 in year 2. In group B, relapse rates were 0.61 in year 1 and 0.50 in year 2 (cladribine). Patients required fewer steroid courses during cladribine periods. The therapeutic efficacy of cladribine was associated with a sustained reduction in lymphocyte count.

A Long-Term Study of Dyslipidemia and Dyslipoproteinemia in Stable Post-Renal Transplant Patients

Background. Dyslipidemia is a major risk factor for atherosclerotic disease in renal transplant patients. Methods. The serum levels of lipids and lipoproteins were determined in the same 12 post-renal transplant patients (TX) 10–29 and 73–122 months after transplantation. Thirteen healthy subjects—i.e., without diabetes, endocrine disease, liver disease, active inflammatory disease, glucose intolerance, malignancy, obesity, and urinary protein—were used as a reference group. TX patients had stable renal function. Twelve patients received cyclosporine A and prednisone, six received lovastatin, and one received rapa and prednisone. Lipids and lipoprotein (apo)AI and B were determined using Roche kits. An anti-apoB antibody was used to separate apoB-containing apoCIII and apoE lipoproteins as triglyceride-rich lipoproteins (TRLs) in the non-HDL fraction from apoCIIInonB and apoEnonB in the HDL fraction. Results. In both groups of post-renal transplant patients, a statistically significant increase of TG, TC, and non-HDL-C levels was observed. Moreover, statistically significant changes were shown in total apoCIII and apoCIIInonB, as well as in TG/HDL-C and apoAI/apoCIII ratios, as compared to the reference group. On the other hand, in TX patients 73–122 months after transplantation, significantly higher concentrations of TC, LDL-C, and especially non-HDL-C were observed. It was shown that apoCIII, apoCIIInonB, apoB:CIII, and lipid and lipoprotein ratios as risk factors of atherosclerosis and renal risk factors were higher in these patients 73–122 months after transplantation. Conclusion. TX patients in a long-term study showed that they had disturbed lipoprotein composition, and its consequence was hyperlipidemia, perhaps partly due to the increased use of immunosuppressants and steroids.

Disturbed lipids, lipoproteins and triglyceride-rich lipoproteins as well as fasting and nonfasting non-high-density lipoprotein cholesterol in post-renal transplant patients.

Serum levels of lipids and lipoproteins were determined in 98 post-renal transplant fasting patients, and lipids and non-high density lipoprotein-cholesterol (non-HDL-C) and lipid ratios in the same post-renal transplant non-fasting patients were compared. The reference group was 87 healthy subjects. All patients were divided into two groups: patients with dyslipidemia (n = 69) and patients with normolipidemic (n = 29). The post-renal transplant patients (TX) with dyslipidemia had a significantly increased concentration of triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), non-HDL-C, apoB, and TRL and lipid ratios, and decreased HDL-C level and lipoprotein ratios. The lipids, lipoproteins, and lipoprotein ratios were significantly beneficial in TX patients with normolipidemic than in those with dyslipidemia. However, TRL concentration and lipid ratios were significantly increased and apoAI/apoCIII significantly decreased as compared to the reference group. The TX patients with dyslipidemia showed a significant correlation between TG and apoB:CIII (r = 0.562, p < 0.001) and apoCIII (r = 0.380, p < 0.004), but those with normolipidemic showed a significant correlation only between TG and apoCIII (r = 0.564, p < 0.008). Regression and Bland-Altman analyses showed excellent correlation between fasting and nonfasting non-HDL-C levels (r = 0.987, R2 + 0.987) in TX patients both with dyslipidemia and normolipidemic. We think the finding that nonfasting labs that are reliable for non-HDL-C as well as total cholesterol is important, as fasting labs are not always available. Disturbances of lipids, lipoproteins, and TRLs depend not only on the kind of treatment, but due to multiple factors can accelerate cardiovascular complications in post-renal transplant patients with dyslipidemia and also with normolipidemic. Further studies concerning this problem should be completed.

Association between moderately oxidized low-density lipoprotein and high-density lipoprotein particle subclass distribution in hemodialyzed and post-renal transplant patients

Disturbances in the metabolism of lipoprotein profiles and oxidative stress in hemodialyzed (HD) and post-renal transplant (Tx) patients are proatherogenic, but elevated concentrations of plasma high-density lipoprotein (HDL) reduce the risk of cardiovascular disease. We investigated the concentrations of lipid, lipoprotein, HDL particle, oxidized low-density lipoprotein (ox-LDL) and anti-ox-LDL, and paraoxonase-1 (PON-1) activity in HD (n=33) and Tx (n=71) patients who were non-smokers without active inflammatory disease, liver disease, diabetes, or malignancy. HD patients had moderate hypertriglyceridemia, normocholesterolemia, low HDL-C, apolipoprotein A-I (apoA-I) and HDL particle concentrations as well as PON-1 activity, and increased ox-LDL and anti-ox-LDL levels. Tx patients had hypertriglyceridemia, hypercholesterolemia, moderately decreased HDL-C and HDL particle concentrations and PON-1 activity, and moderately increased ox-LDL and anti-ox-LDL levels as compared to the reference, but ox-LDL and anti-ox-LDL levels and PON-1 activity were more disturbed in HD patients. However, in both patient groups, lipid and lipoprotein ratios (total cholesterol (TC)/HDL-C, LDL-C/HDL-C, triglyceride (TG)/HDL-C, HDL-C/non-HDL-C, apoA-I/apoB, HDL-C/apoA-I, TG/HDL) were atherogenic. The Spearman’s rank coefficient test showed that the concentration of ox-LDL correlated positively with HDL particle level (R=0.363, P=0.004), and negatively with TC (R=−0.306, P=0.012), LDL-C (R=−0.283, P=0.020), and non-HDL-C (R=−0.263, P=0.030) levels in Tx patients. Multiple stepwise forward regression analysis in Tx patients demonstrated that ox-LDL concentration, as an independent variable, was associated significantly positively with HDL particle level. The results indicated that ox-LDL and decreased PON-1 activity in Tx patients may give rise to more mildly-oxidized HDLs, which are less stable, easily undergo metabolic remodeling, generate a greater number of smaller pre-β-HDL particles, and thus accelerate reverse cholesterol transport, which may be beneficial for Tx patients. Further studies are necessary to confirm this.

Disturbed lipoprotein composition in non-dialyzed, hemodialysis, continuous ambulatory peritoneal dialysis and post-transplant patients with chronic renal failure.

Abstract Studies were carried out in 183 non-dialyzed, 123 hemodialysis, 81 continuous ambulatory peritoneal dialysis and 35 post-transplant patients and in 103 healthy subjects as a reference group. Lipids and apolipoprotein (apo)AI and apoB were determined using Roche kits. An anti-apoB antibody was used to separate apoB-containing apoCIII and apoE-triglyceride-rich lipoprotein (TRL) in the non-high-density lipoprotein (non-HDL) fraction from apoCIIInonB and apoEnonB in the HDL fraction in four groups of patients with chronic renal failure (CRF) and healthy subjects. Multivariate linear regression analysis was used to investigate the relationship between triglyceride (TG) or HDL-cholesterol (HDL-C) concentrations and lipoproteins. Dyslipidemia varied according to the degree of renal insufficiency, the type of dialysis and therapy regime in CRF patients. Lipoprotein disturbances were manifested by increased TG, non-HDL-C and TRL concentrations, and decreased HDL-C and apoAI concentrations, whereas post-renal transplant patients showed normalization of lipid and lipoprotein profiles, except for TG levels and total apoCIII and apoCIIInonB. The present study indicates that CRF patients have disturbed lipoprotein composition, and that hypertriglyceridemia and low HDL-C concentrations in these patients are multifactorial, being secondary to disturbed lipoproteins. The method using anti-apoB antibodies to separate apoB-containing lipoproteins in the non-HDL fraction from non-apoB-containing lipoproteins in HDL can be used in the diagnosis and treatment of patients with progression of renal failure or atherosclerosis. The variability of TG and HDL-C concentrations depends on the variability of TRL and cholesterol-rich lipoprotein concentrations, but the decreases in TG and increases in HDL-C concentrations are caused by apoAI concentration variability. These relationships, however, need to be confirmed in further studies.

Plasma lipoproteins in patients with chronic renal failure (CRF)

The clinical picture in chronic renal failure (CRF) shows great variability depending on age, sex, aetiology of disease, grades of renal injury and type of treatment.Significant increases of triglycerides (TG), low-density lipoprotein cholesterol (LDL-chol) and apo B concentrations, significant decreases of high-density lipoprotein cholesterol (HDL-chol) levels and apo A and apo AI concentrations, and no significant changes in total cholesterol (TC) have been shown in CRF patients. Significant increases of TC/HDL-chol, LDL-chol/HDL-chol, apo B/apo AI and apo B/LDL-chol ratios were also demonstrated. That indicates a high risk of atherosclerosis even when total cholesterol levels are in the normal range. There were highly significant and positive correlations between TC/HDL-chol and LDL-chol/HDL-chol ratios, apo B and LDL-chol concentrations as well as between the apo B/apo AI and LDL-chol/HDL-chol ratios.