Inflammatory pathways in patients with heart failure and preserved ejection fraction

Immune activation is well established in patients with chronic heart failure and reduced ejection fraction (HF and reduced EF) and is associated with an impaired prognosis. Patients with heart failure and preserved ejection fraction (HF and preserved EF) have an impaired prognosis as well. It is not known whether they have signs of immune activation.

Methods

We studied patients with HF and preserved EF (n = 17, NYHA II [n = 7]/III [n = 10]) and patients with HF and reduced EF (n = 17 NYHA II [n = 1]/III [n = 16]) and 20 controls. Echocardiography demonstrated preserved ejection fraction (LVEF 59 ± 9%), but LV hypertrophy in patients with preserved EF as compared with patients with reduced EF (LVEF 23 ± 5%). We evaluated levels of TNFα, its receptors (sTNFR-1 and 2), IL-6, IL-10 and NT-proBNP.

Results

TNFα, was highest in HF with reduced EF (2.87 ± 0.65 vs 1.67 ± 0.58 pg/mL, p < 0.001) compared to preserved EF and similar between HF with preserved EF and controls. However, sTNFR1 (1618 ± 384 vs 1017 ± 302 pg/mL, p < 0.001) and sTNFR2 levels (3554 ± 916 vs 2041 ± 586 pg/mL, p < 0.001) in HF with preserved EF were significantly higher compared with controls. The same was true for IL-6, IL-10 and NT-proBNP. The highest cytokine and NT-proBNP levels were present in HF with reduced EF. There was a negative correlation between TNFα, and LVEF (r = −  0.700; p < 0.0001) and positive correlations between sTNFR1 and 2 with NT-proBNP.

Conclusion

Patients with HF and preserved EF already show signs of systemic-immune activation which may contribute to the impaired prognosis and the progression to HF with reduced EF.     

Cystatin C--a marker of peripheral atherosclerotic disease?

It has been suggested that Cystatin C, besides its function as a marker of glomerular filtration, could be an independent marker of cardiovascular disease. However, studies on this topic are few and results have been indecisive. Our aim was to further investigate the subject of Cystatin C as an independent marker of peripheral atherosclerotic disease.

Method

Blood samples were analysed for serum Cystatin C, IL6, CRP and creatinine in 103 males with peripheral arterial disease (PAD) and 96 controls matched for age and sex. Creatinine clearance (CCr) was calculated according to Cockcroft's formula and estimated glomerular filtration rate (eGFR) was calculated according to MDRD formula.

Results

Cystatin C-concentration was higher in PAD-patients compared to controls; 1.09 ± 0.40 vs. 0.95 ± 0.17 mg/L (p < 0.01). There was no difference in CCr; 81 ± 27 vs. 82 ± 22 mL/min or eGFR; 76 ± 21 vs. 79 ± 14 mL/min. Cystatin C correlated to CCr, log IL-6 and log CRP in both patients (r = −0.60, p < 0.001), (r = 0.35, p < 0.001) and (r = 0.30, p < 0.01) and controls (−0.44, p < 0.001), (0.38, p < 0.001) and (r = 0.32, p < 0.01), respectively. In an analysis of covariance, corrected for difference in eGFR, Cystatin C remained higher in PAD-patients compared to controls; 1.09 (C.I. 1.04–1.14) vs. 0.96 (C.I. 0.90–1.01).

Conclusion

Cystatin C-concentration, corrected for differences in eGFR, IL-6 and CRP values, is higher in PAD-patients compared to controls. Our finding suggests that Cystatin C may be an independent marker of atherosclerotic disease apart from its relation to kidney function.     

Low-dose interferon-alpha accelerates atherosclerosis in an LDL receptor-deficient mouse model

Background: Solid evidence suggests that atheroscleosis is associated with immune reactions. Most of the activated T cells in the plaque are T helper 1 subtype (Th1), which secrete interferon-γ (IFN-γ), now generally accepted as a proatherogenic cytokine. Interferon-α (IFN-α) has been found to inhibit the secretion of IL-12 and IFN-γ and to increase IL-10 production. It may, therefore, be atheroprotective. The aim of the present study was to clarify the effect of IFN-α on atherogenesis in a transgenic mouse model of atherosclerosis. Methods: 8-week-old low-density lipoprotein (LDL) receptor-deficient mice were allocated randomly into treatment and control groups (n=13 each). The treatment group received 1000 units of IFN-α i.p. every other day for 5 weeks and the control mice received 0.9% NaCl. The mice were fed a Western diet. Results: The IFN-α-treated and the control mice showed a similar weight gain (mean 3.9±1.0 g vs. 3.4±1.8 g, respectively). Treatment with IFN-α significantly increased the plasma cholesterol levels in both treated and untreated mice (mean 31.03±5.53 mmol/l vs. 24.91±6.03 mmol/l, respectively; p<0.022) as well as the plasma triglyceride levels (mean 4.79±1.57 mmol/l vs. 3.10±1.85 mmol/l, respectively; p<0.033). The IFN-α treated mice had a significantly increased atherosclerotic plaque area (mean 61,590±22,368 μm² vs. 37,272±15,469 μm², respectively; p<0.008). Conclusion: The putative atheroprotective effect of IFN-α by the decrease in IL-10 and IFN-γ is abolished by hyperlipidemia. Therefore, the net effect of IFN-α in this murine model is the exacerbation of atherosclerosis.     

Alterations in cell adhesion molecules and other biomarkers of cardiovascular disease in patients with metabolic syndrome

Metabolic syndrome is considered a hyperinsulinemic and inflammatory state closely associated to endothelial dysfunction causing an increased incidence of ischemic cardiovascular events and high mortality. The main objective of the present study was to determine whether leukocitary and soluble cell adhesion molecules were altered in patients with metabolic syndrome in comparison with control subjects. Cell adhesion molecules, mainly of leukocitary location, have been not previously evaluated in specifically designed cross-sectional studies involving male patients with metabolic syndrome. Moreover, other circulating markers of different candidate atherogenic risk parameters were also studied and the potential existence of a progressive relation between the number of metabolic syndrome components and the above mentioned biomarkers was analyzed. Thirty one male patients with metabolic syndrome (ATPIII definition) and 56 male control subjects were studied. We evaluated different markers of insulin resistance, inflammation and atherosclerosis, as well as protective factors. Patients with metabolic syndrome showed (a) hypoadiponectinemia (4551 ± 2302 ng/ml vs. 5865 ± 2548 ng/ml, respectively; p < 0.05), (b) an atherogenic lipid and lipoprotein profile, (c) altered HDL chemical composition accompanied by higher cholesteryl ester-triglyceride interchange carried out by CETP, (d) diminished Lp-PLA₂ activity (6.5 ± 1.9 vs. 7.3 ± 2.2, p < 0.05, respectively), antioxidant enzyme related with LDL oxidation, which was positively associated with QUICKI and negatively with VCAM-1 and lymphocyte CD18, and (e) high soluble (VCAM-1: 17 ± 5 vs. 13 ± 4 ng/ml, respectively; p < 0.0005) and leukocyte adhesion molecule expression (monocyte CD54: 52 ± 15 vs. 45 ± 12 arbitrary units, respectively; p < 0.0005; and lymphocyte CD49d: 312 ± 56 vs. 284 ± 64 arbitrary units, respectively; p < 0.05). The increment in leukocyte and soluble cell adhesion molecules, crucial for leukocyte interaction with the endothelium and migration into the artery wall, in combination with the other disorders described above reinforce the presence of a clinical status with high propensity to type 2 diabetes and atherosclerotic cardiovascular disease.     

Type of antidepressant therapy and risk of type 2 diabetes in people with depression

We evaluated the influence of baseline diabetic knowledge on clinical course of type 1 diabetes treated with intensive functional insulin therapy (IFIT) from the onset of the disease. 86 subjects with newly diagnosed type 1 diabetes, aged 23.4 ± 5.1 attended a five-day structured training program in IFIT at baseline, followed by a test consisting of 20 questions. Patients were divided into subgroups according to test results: group A > 16, group B 12–16 and group C < 12 scores. At follow-up (7.1 ± 1.5 years) metabolic control and development of microangiopathy were assessed. Patients with low knowledge at baseline had higher HbA1c levels than subjects with higher knowledge (group C: 9.2 ± 1.9 vs. group A: 7.7 ± 1.5%, p < 0.05 and vs. group B: 7.8 ± 1.6%, p < 0.05), higher BMI (group C: 23.9 ± 3.2 vs. group A: 21.8 ± 3.1 kg/m², p < 0.05) and lower HDL-cholesterol level (group C: 1.8 ± 0.5 vs. group A: 2.0 ± 0.3 mmol/l, p < 0.05). Patients with retinopathy and albuminuria at follow-up had lower level of diabetic knowledge at baseline (respectively: 12.5 ± 3.6 vs. 14.2 ± 3.3 scores, p < 0.05; and 12.6 ± 2.9 vs. 14.1 ± 3.5 scores, p < 0.05). The development of microangiopathy was associated with lower diabetic knowledge (RR = 3.71; 95%CI: 1.15–12.01, p = 0.02 for retinopathy and RR = 4.33; 95%CI: 0.98–19.10, p = 0.04 for microalbuminuria). The higher diabetic knowledge at baseline the better metabolic control and lower risk of microangiopathy in the future.     

Proinflammatory cytokine activation is linked to apoptotic mediator, soluble Fas level in patients with chronic heart failure

The Fas/Fas Ligand system is a major apoptosis signaling pathway that is up-regulated in patients with chronic heart failure (CHF). Serum soluble Fas (sFas) levels increase in proportion to the CHF severity and may have prognostic value, therefore, sFas is a promising biomarker of heart failure. In this study, we attempted to identify the determinants of sFas levels in patients with CHF. Serum levels of tumor necrosis factor (TNF)-α and its soluble receptors (sTNF-R1 & sTNF-R2), interleukin (IL)-6, soluble IL-6 receptor (sIL-6R), glycoprotein (gp)130, and sFas were measured in 106 patients with CHF and 39 controls. All subjects performed a symptom-limited cycle ergometer exercise test with expired gas analysis. CHF patients had higher levels of TNF-α, sTNF-R1, sTNF-R2, IL-6, and gp130. Serum levels of sFas (controls versus CHF; 2.60 ± 0.88 versus 3.38 ± 1.23 ng/mL, P = 0.0004) were higher in CHF. On univariate analysis, age (P = 0.0003), NYHA functional class (P = 0.0012), peak VO2 (P < 0.0001), plasma norepinephrine (P = 0.0013), log IL-6 (P < 0.0001), log TNF-α (P = 0.0002), log sTNF-R1 (P < 0.0001), and log TNF-R2 (P < 0.0001) were significantly related to log sFas levels. Multivariate analysis showed that age and log IL-6 and log sTNF-R1 levels were independently associated with log sFas levels (overall R = 0.603, P < 0.0001). Serum levels of sFas were increased in patients with CHF, and age and serum IL-6 and sTNF-R1 levels were independent determinants of sFas levels. These data suggest that proinflammatory cytokine activation is linked to the Fas/Fas Ligand system in patients with CHF.     

Effect of selective and nonselective β-blockers on resting energy production rate and total body substrate utilization in chronic heart failure

Background: In chronic heart failure (CHF) β-blockers reduce myocardial oxygen consumption and improve myocardial efficiency by shifting myocardial substrate utilization from increased free fatty acid oxidation to increased glucose oxidation. The effect of selective and nonselective β-blockers on total body resting energy production rate (EPR) and substrate utilization is not known. Methods: Twenty-six noncachectic patients with moderately severe heart failure (New York Heart Association class II or III, left ventricular ejection fraction < 0.40) were treated with carvedilol (37.5 ± 13.5 mg/12 h) or bisoprolol (5.4 ± 3.0 mg/d) for 6 months. Indirect calorimetry was performed before and after 6 months of treatment. Results: Resting EPR was decreased in carvedilol (5.021 ± 0.803 to 4.552 ± 0.615 kJ/min, P < .001) and bisoprolol group (5.230 ± 0.828 to 4.978 ± 0.640 kJ/min, P < .05; nonsignificant difference between groups). Lipid oxidation rate decreased in carvedilol and remained unchanged in bisoprolol group (2.4 ± 1.4 to 1.5 ± 0.9 mg m²/kg min versus 2.7 ± 1.1 to 2.5 ± 1.1 mg m²/kg min, P < .05). Glucose oxidation rate was increased only in carvedilol (2.6 ± 1.4 to 4.4 ± 1.6 mg m²/kg min, P < .05), but did not change in bisoprolol group. Conclusions: Both selective and nonselective β-blockers reduce total body resting EPR in noncachectic CHF patients. Carvedilol compared to bisoprolol shifts total body substrate utilization from lipid to glucose oxidation.     

Immunohistochemical analysis of hepatic interferon alpha-beta receptor level: relationship between receptor expression and response to interferon therapy in patients with chronic hepatitis C

Background/Aims: This study aimed to determine the expression level of interferon alpha/beta (IFN-α/β) receptor in the liver immunohistochemically and evaluate its usefulness in predicting the outcome to IFN therapy in patients with chronic hepatitis C.Methods: The level of IFN-α/β receptor expression was determined in immunoperoxidase-stained pretreatment sections of 55 chronic hepatitis C patients later treated with IFN. We used liver biopsy specimens and mouse monoclonal anti-human IFN-α/β receptor antibody. Quantitative analysis of immunostaining was performed by image analysis software. The level of IFN-α/β receptor was expressed as Unit (U). Sustained responders were patients who showed persistent disappearance of serum HCV-RNA during the 6-month period after treatment, while non-responders showed persistence of viremia after therapy.Results: Positive immunostaining was observed in the cytoplasm of hepatocytes. The mean expression level of hepatic IFN-α/β receptor in sustained responders (2.65±1.11 U, n=15) was significantly (p<0.001) higher than in non-responders (1.61±1.05 U, n=40). A significant decrease in IFN-α/β receptor expression level was observed in patients with advanced liver fibrosis. In patients with low level viremia (pretreatment serum HCV-RNA <1 Meq/ml, n=18), the level of IFN-α/β receptor in sustained responders (2.89±1.12 U, n=11) was significantly (p<0.01) higher than in non-responders (0.93±0.33 U, n=7).Conclusions: Our results suggest that measurement of the level of hepatic IFN-α/β receptor in patients with chronic hepatitis C might be useful for predicting the response to IFN therapy. Resistance to IFN therapy in patients with chronic hepatitis C might be due to low levels of hepatic IFN-α/β receptor.     

Rosiglitazone improves insulin sensitivity with increased serum leptin levels in patients with type 2 diabetes mellitus

Rosiglitazone (RSG) is known to be an agonist for the peroxisome proliferator-activated receptor-γ (PPARγ) and promotes differentiation of pre-adipocytes into adipocytes. Leptin is highly correlated with adiposity, while the activation of PPARγ is known to inhibit Lep gene expression and leptin release. This study was performed to evaluate the relationship between changes in circulating leptin levels, insulin sensitivity and regional adiposity after RSG treatment. Two hundred fifty-one type 2 diabetic patients (176 men and 75 women) who had been treated with sulfonylurea and/or metformin received 4 mg of RSG daily, in addition to the previous medications. Before and after RSG treatment (average duration 5.6 ± 0.9 months), indices of insulin resistance, metabolic parameters, and serum leptin and adiponectin levels were measured. Abdominal subcutaneous fat thickness (SFT_max) and visceral fat thickness were measured by sonography. After RSG treatment, HOMA-IR index decreased significantly (2.82 ± 1.94 vs. 2.01 ± 1.58), while BMI and SFT_max increased, and leptin (4.72 ± 3.77 vs. 5.69 ± 4.30 ng/ml) and adiponectin levels (7.54 ± 10.20 vs. 12.89 ± 10.13 μg/ml) increased. The increase in serum leptin correlated with an increase in SFT_max (r = 0.511, p < 0.001) and with a reduction in HOMA-IR (r = −0.368, p < 0.001). The correlation of Δleptin with ΔHOMA-IR and with ΔSFT_max was higher in females and among insulin-resistant subjects. In conclusion, RSG improves the insulin sensitivity with increased serum leptin levels in patients with type 2 diabetes mellitus, which is related to an increase in subcutaneous adiposity.     

An experimental study on ulcerative colitis as a potential target for probiotic therapy by Lactobacillus acidophilus with or without “olsalazine”

Traditional medical treatments for ulcerative colitis (UC) are still compromised by its adverse effects and not potent enough to keep in remission for long-term periods. So, new therapies that are targeted at specific disease mechanisms have the potential to provide more effective and safe treatments for ulcerative colitis. Probiotics is recently introduced as a therapy for ulcerative colitis. In the present study, Lactobacillus acidophilus was selected as a probiotic therapy to investigate its effects in oxazolone-induced colitis model in rats that mimics the picture in human. The rats were grouped (8 rats each) as normal control group (Group I), Group II served as untreated oxazolone-induced colitis, Group III oxazolone-induced colitis treated with probiotic L. acidophilus (1 × 10⁷ colony-forming units (CFU)/mL/day oral for 14 days), Group IV oxazolone-induced colitis treated with olsalazine (60 mg/kg/day oral for 14 days), Group V oxazolone-induced colitis treated with probiotic L. acidophilus and olsalazine in the same doses and duration. Disease activity index (DAI) was recorded, serum levels of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and intrleukin-6 (IL-6) was assessed as inflammatory markers and the histopathological picture of the colon of each rat was studied. Disease activity index (DAI) showed significant positive correlation with the elevated serum levels of CRP (r = 0.741, p < 0.05), TNF-α (r = 0.802, p < 0.05) and IL-6 (r = 0.801, p < 0.05). Treatment with either L. acidophilus (group III) or olsalazine (group IV) resulted in significant reduction in serum levels of CRP, TNF-α and IL-6, as well as disease activity index (DAI). Treatment with combination of L. acidophilus and olsalazine (group V) offered more significant reduction in serum levels of CRP, TNF-α, IL-6 and disease activity index (DAI) when compared to either group II (untreated group), group III (treated with L. acidophilus) or group IV (treated with olsalazine). So, it was concluded that L. acidophilus probiotic could be recommended as adjuvant therapy in combination with olsalazine to achieve more effective treatment for ulcerative colitis. For application in human, this needs to be verified in further clinical studies.     

Experimental arthritis: Effect on growth parameters and total skeletal calcium

Aim of the study was to investigate the possible mechanisms leading to stunted growth and osteoporosis in experimental arthritis. Fourty-two female rats of 7–8 weeks of age were randomly assigned to three groups of 14 animals each: (a) controls; (b) adjuvant-inoculated (AA); and (c) adjuvant-inoculated rats receiving 10 mg cyclosporin A (CsA) orally for 30 days. Biological parameters studied were: hindpaw swelling; vertebral length progression expressed as Δ increments between days 1 and 30 as a parameter of skeletal growth, and estimation of total skeletal mineral content by dual energy X-ray absorptiometry (n = 10 each group) on day 30. Endocrine parameters measured were pulsatile release of growth hormone (rGH) on day 30 following jugular cannulation and measurement of insulin-like growth factor (IGF-1) in pooled plasma from rGH profiles.Results can be summarized as follows: Untreated AA rats exhibited local signs of inflammation in comparison with controls (hindpaw diameter 8.1–8.9 mm vs. 5.3–5.6 mm in controls). Treatment with CsA normalized this parameter (4.9–5.6 mm). Vertebral growth was significantly retarded in AA rats in comparison with controls (214 ± 32 vs. 473 ± 33 μm; p < 0.001). Administration of CsA normalized vertebral size increment with a clear tendency to overgrowth (523 ± 43 μm, n.s.). There was also a marked reduction in total skeletal mineral content in diseased (AA) rats as compared to controls (5.8 ± 0.1 vs. 7.5 ± 0.1 g [OH-apatite]; p < 0.001), and a moderate but significant increment above controls in the group receiving CsA (8.0 ± 0.1 vs. 7.5 ± 0.1 g [OH-appatite]; p < 0.04). Integrated rGH profiles exhibited a significant fall in arthritic rats and were completely restored to normal under CsA treatment. A trend toward higher rGH values was observed in the latter group (2908 ± 554 in AA vs. 8317 ± 1492 ng/ml/240 min in controls; p < 0.001, and 10940 ± 222 ng/ml/240 min, n.s. in the CsA group). There was a good correlation between skeletal growth and rGH pulsatility (r = 0.81; p < 0.001). IGF-1 followed a similar pattern (630 ± 44 in AA vs. 752 ± 30 ng/ml in controls; p < 0.04, and 769 ± 59 ng/ml in the CsA group, n.s. vs. controls). Thus, a clear tendency to skeletal overgrowth following treatment was observed in agreement with the hormonal data. It can therefore be concluded that, in experimental arthritis, attenuated GH-spiking and reduced circulating IGF-1 appear to be causally related to growth retardation, probably mimicking signs and symptoms observed in juvenile arthritis. Therapy with CsA is followed by normalization of hormonal and biological parameters accompanied by a catch up phenomenon in skeletal growth which is also observed clinically in juvenile arthritis. Generalized osteopenia is a prominent feature seemingly connected with the growth abnormalities as they parallel each other during the evolution of the disease and respond equally to therapy.     

Human neutrophil-pulmonary microvascular endothelial cell interactions in vitro: differential effects of nitric oxide vs. peroxynitrite

Sepsis-induced acute lung injury is characterized by activation and injury of pulmonary microvascular endothelial cells (PMVEC), increased neutrophil–PMVEC adhesion and migration, and trans-PMVEC high-protein edema. Inducible NO synthase (iNOS) inhibits septic murine neutrophil migration in vivo and in vitro. The effects of NO in human neutrophil–PMVEC interactions are not known. We isolated human PMVEC using magnetic bead-bound anti-PECAM antibody. Confluent PMVEC at passage 3–4 were co-cultured with human neutrophils for assessment of neutrophil–PMVEC adhesion, and trans-PMVEC neutrophil migration and Evans-Blue dye-labeled albumin leak. Two NO donors (spermine-NONOate, S-nitroso-N-acetylpenicillamine) attenuated both cytomix-enhanced neutrophil–PMVEC adhesion by 64 ± 14% (p < 0.01) and 32 ± 3% (p < 0.05), respectively, and cytomix-induced trans-PMVEC neutrophil migration by 85 ± 16% (p < 0.01) and 43 ± 5% (p < 0.01), respectively. Correspondingly, iNOS inhibition with 1400W enhanced cytomix-stimulated neutrophil migration by 52 ± 3% (p < 0.01), but had no effect on neutrophil–PMVEC adhesion. Conversely, a peroxynitrite donor (SIN-1) increased both neutrophil–PMVEC adhesion (38 ± 2% vs. 14 ± 1% control, p < 0.01) and trans-PMVEC neutrophil migration; with both effects were completely inhibited by scavenging of NO, superoxide, or peroxynitrite (p < 0.05 for each). Scavenging of peroxynitrite also eliminated cytomix-induced neutrophil adhesion and migration. Blocking CD18-dependent neutrophil adhesion prevented cytomix-stimulated trans-PMVEC EB-albumin leak (p < 0.05), while inhibiting neutrophil migration paradoxically enhanced cytomix-stimulated EB-albumin leak (11 ± 1% vs. 7 ± 0.5%, p < 0.01). FMLP-induced neutrophil migration had no effect on trans-PMVEC EB-albumin leak. In summary, we report differential effects, including the inhibitory action of NO and stimulatory effect of ONOO⁻ on human neutrophil–PMVEC adhesion and trans-PMVEC migration under cytomix stimulation. Moreover, neutrophil–PMVEC adhesion, but not trans-PMVEC migration, contributes to human PMVEC barrier dysfunction.     

Increased adiponectin synthesis in the visceral adipose tissue in men with coronary artery disease treated with pravastatin: a role of the attenuation of oxidative stress

Pravastatin is reported to increase the adiponectin level in humans, but the mechanism remains unclear. We examined plasma and gene expressions of adiponectin, tumor necrosis factor (TNF)-α, interleukin (IL)-6 and protein carbonyl level, an indicator of oxidative stress, in visceral and subcutaneous adipose tissue from 32 patients with coronary artery disease undergoing coronary artery bypass grafting (CABG). Fourteen patients with serum LDL-cholesterol level >100 mg/dl were treated with pravastatin at 10 mg/day for 2 months before CABG (Statin), and the other 18 with LDL-cholesterol ≤100 mg/dl were not (Control). The plasma adiponectin level was higher in the Statin than the Control group (P < 0.05), but TNF-α and IL-6 levels were not different. Adiponectin gene expression in visceral tissue was 3-fold higher in the Statin than the Control group (P < 0.01), but was not different in subcutaneous tissue. TNF-α and IL-6 gene expressions in each tissue were not different between the 2 groups. Protein carbonyl levels in plasma and visceral tissue were lower in the Statin than the Control group (both, P < 0.05). Thus, adiponectin expression and generation in visceral adipose tissue is increased in men with coronary artery disease treated with pravastatin. Pravastatin-initiated attenuation of oxidative stress could be involved.     

Effects of muscle strength and aerobic training on basal serum levels of IGF-1 and cortisol in elderly women

The aim of this study was to compare the effects of muscle strength and aerobic training on the basal serum levels of IGF-1 and cortisol in elderly women. The subjects were divided in three groups as follows. 1. Strength training group (SG) submitted to the weight training called 1-repetition maximum test (1-RM, 75–85%). This group contained 12 subjects of mean age = 66.08 ± 3.37 years; and body mass index (BMI) = 26.0 ± 3.72 kg/m². (2) Aerobic training group (AG) submitted to aquatic exercise; they were 13 subjects of the mean age = 68.69 ± 4.70 years; and BMI = 29.19 ± 2.96 kg/m². (3) A control group (CG) of 10 subjects, of mean age = 68.80 ± 5.41 years; BMI = 29.70 ± 2.82 kg/m². The training periods were 12 weeks, Fasting blood was analyzed to measure IGF-1 and basal cortisol levels (by chemiluminescence method), both at the beginning and the end of the intervention. Student's t-test revealed increased IGF-1 in the SG (p < 0.05) compared to the other two groups. Repeated-measure ANOVA showed also elevated IGF-1 (p < 0.05) in the SG compared to the other groups (AG and CG). There were no differences in cortisol levels. In conclusion, high-intensity training caused changes in IGF-1. This suggests that strength training may provoke anabolic effects in elderly individuals.     

No correlation and low agreement of imaging and inflammatory atherosclerosis' markers in familial hypercholesterolemia

Our purpose was to study the determinants of coronary and carotid subclinical atherosclerosis, aortic stiffness and their relation with inflammatory biomarkers in familial hypercholesterolemia (FH) subjects. Furthermore, we evaluated the agreement degree of imaging and inflammatory markers’ severity used for coronary heart disease (CHD) prediction. Coronary calcium scores (CCS), carotid intima media thickness (IMT), carotid-femoral pulse wave velocity (PWV), C reactive protein (CRP) and white blood cells count (WBC) were determined in 89 FH patients (39 ± 14 years, mean LDL-C = 279 mg/dl) and in 31 normal subjects (NL). The following values were considered as imaging and biomarkers’ severity: CCS > 75th% for age and sex, IMT > 900 μm, PWV > 12 m/s, and CRP > 3 mg/l.Coronary artery calcification (CAC) prevalence and severity, IMT, PWV and WBC values were higher in FH than in NL (all parameters, p < 0.05). After multivariate analysis, the following variables were considered independent determinants of (1) IMT: systolic blood pressure, 10-year CHD risk by Framingham risk scores (FRS) and apolipoprotein B (r² = 0.33); (2) PWV: age (r² = 0.35); (3) CAC as a continuous variable: male gender and LDL-cholesterol year score (LYS) (r² = 0.32); (4) presence of CAC as dichotomous variable: FRS (p = 0.0027) and LYS (p = 0.0228). With the exception of a moderate agreement degree between IMT and PWV severity (kappa = 0.5) all other markers had only a slight agreement level (kappa < 0.1). In conclusion, clinical parameters poorly explained IMT, CAC and PWV variability in FH subjects. Furthermore, imaging markers and inflammatory biomarkers presented a poor agreement degree of their severity for CHD prediction.     

Correlation between serum concentrations of soluble Fas (CD95/Apo-1) and IL-18 in patients with systemic lupus erythematosus

Recent researches suggest that imbalance in apoptotic process may lead to susceptibility to systemic lupus erythematosus (SLE). Production of pro-inflammatory cytokines, such as IL-18, has important role in autoimmune process in lupus. There are cumulative data on the pro-apoptotic role of IL-18, in the Fas-mediated apoptosis. Soluble Fas (Apo/1-CD95) is a marker of apoptosis that appears to increase in serum of SLE patients. Previous studies demonstrated increasing serum concentrations of soluble Fas (sFas) and IL-18 in SLE. To assess the correlation between serum concentrations of sFas and IL-18 in SLE patients, 114 SLE patients were selected randomly at the different stages of disease activity according to SLEDAI2K. IL-18 and sFas serum concentrations were compared in patients and fifty randomly selected healthy volunteers. The correlations of IL-18 and sFas serum concentrations with SLEDAI2K and with each other were evaluated in patients. There were a significant difference between serum concentrations of sFas and IL-18 in the case and control groups (P = 0.001). There was a significant correlation between serum concentrations of sFAS and IL-18 in SLE patients (P < 0.0001, r = 0.411). The elevations of IL-18 and sFas(Apo/1-CD95) serum concentrations in SLE patients are significantly correlated.     

Increased serum pigment epithelium-derived factor levels in type 1 diabetic patients with diabetic retinopathy

Serum pigment epithelium-derived factor (PEDF) levels were significantly higher in type 1 diabetic patients with retinopathy (n = 20, 10.38 ± 3.87 μg/ml) compared to the patients without it (n = 57, 7.68 ± 2.80 μg/ml) (p = 0.0013). Elevated PEDF levels may be related to the progression of diabetic retinopathy.     

Serum transferrin receptors: Distribution and diagnostic performance in pre-school children

Soluble transferrin receptors have gained interest in the field of diagnosing anemias. Reference ranges differ according to the method used for the quantification of sTfR. We aim to explore the distributional properties and diagnostic performance of sTfR in pre-school healthy children as well as in children with β-thalassemia carriers, iron deficiency with normal hematological phenotype (ID) and iron deficiency anemia (IDA). Circulating sTfR as well as biochemical and hematological indices were determined in 521 pre-school children and four groups (normal children, β-thalassemia traits, ID and IDA) were formed. Diagnostic performance and distribution of sTfR according to age and in relation to several parameters were evaluated in every group. Three hundred eighty one children (261 normal, 60 β-thalassemia traits, 44 ID and 16 IDA) aged 1–6 years were included. We found that distribution of sTfR differed significantly among the four groups (Kruskal Wallis p < 0.001) with children in the normal group exhibiting lower concentrations compared to all other. A negative correlation between sTfR and age occurred in the normal (β = − 0.12, p < 0.001) and the ID groups (β = − 0.13, p = 0.035). In the β-thal and IDA groups sTfR is correlated to HbA₂ (β = 0.34, p = 0.001) and ferritin (Spearman's rho = − 0.6, p = 0.014) respectively. An area under the curve equal to 0.63 was achieved by sTfR in distinguishing between normal and ID children. Sensitivity and specificity were 70.5% and 50% respectively at a cut-off of 2.5 mg/l. Levels of sTfR are negatively correlated to age in pre-school children while dyserythropoietic procedures like β-thal, ID, and IDA significantly affect them. These findings indicated that the accuracy of sTfR in diagnosing ID from normal children is limited. Standardization will allow the use of formulas that combine sTfR and ferritin which are of greater diagnostic value than sTfR alone.     

The Role of Fas/Fas Ligand System in the Pathogenesis of Liver Cirrhosis and Hepatocellular Carcinoma

Background

The Fas receptor/ligand system including soluble forms is the most important apoptotic initiator in the liver. Dysregulation of this pathway may contribute to abnormal cell proliferation and cell death and is regarded as one of the mechanisms preventing the immune system from rejecting the tumor cells.

Objectives

To analyze the role of Fas system Fas/ Fas ligand (Fas/ FasL) in the multi-step process of hepatic fibrosis/carcinogenesis, and to use of the serum markers as possible candidate biomarkers for early detection of hepatocellular carcinoma (HCC).

Patients and Methods

Ninety patients were enrolled: 30 cases of chronic hepatitis C (CHC) without cirrhosis, 30 cases of CHC with liver cirrhosis, and 30 cases of HCC and hepatitis V virus (HCV) infection. Ten wedge liver biopsies, taken during laparoscopic cholecystectomy, were served as normal controls. Serum soluble Fas (sFas) levels were measured using ELISA technique; Fas and FasL proteins were detected in hepatic tissue by indirect Immuno-histochemical technique (IHC); electron microscopic (EM) and immune electron microscopic examinations were performed for detection of Fas expression on lymphocytes.

Results

Hepatic expression of both Fas and FasL as well as expression of Fas on separated lymphocytes were significantly increased in the diseased groups (P < 0. 01) compared to the control specimens. The highest expression was noticed in CHC specimens, particularly with the necro-inflammatory activity and advancement of the fibrosis. The sFas in cirrhotic patients and HCC were significantly higher than that in normal controls and CHC without cirrhosis group (P < 0.01).

Conclusions

Apoptosis and the Fas system were significantly involved in the process of converting liver cirrhosis into hepatocellular carcinoma. Down-regulation of Fas expression, up regulation of FasL expression in hepatocytes, and elevation of serum sFas levels were important in tumor evasion from immune surveillance, and in hepatic carcinogenesis.