Early increase of oxidative stress and soluble CD40L in children with hypercholesterolemia.

OBJECTIVES: The aim of the study was to analyze the behavior of oxidative stress and its interplay with CD40L, a protein that is implicated in atherosclerosis, in hypercholesterolemic children. BACKGROUND: Oxidative stress has been suggested to play a major role in premature atherosclerosis. METHODS: Forty-one children with hypercholesterolemia (mean age 9.28 +/- 0.5 years) and 40 children with normocholesterolemia (mean age 9.02 +/- 0.69 years) were matched for gender and age. Within each group, children were classified as having or not having a family history of cardiovascular disease. Serum levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative stress, and plasma levels of soluble CD40L (sCD40L) were measured in each child. In a subgroup of children with high (n = 8) or normal (n = 8) levels of serum cholesterol, platelet p38 mitogen-activated protein (MAP) kinase phosphorylation, a protein involved in the activation of nicotinamide adenine dinucleotide phosphate oxidase, was determined. RESULTS: Children with hypercholesterolemia had higher values of 8-OHdG and sCD40L compared with control subjects (0.55 +/- 0.06 ng/ml vs. 0.21 +/- 0.02 ng/ml, p < 0.001 and 0.55 +/- 0.04 ng/ml vs. 0.19 +/- 0.03 ng/ml, p < 0.001, respectively). A significant correlation between 8-OHdG and sCD40L was observed in children with high (r = 0.676, p < 0.001) or normal (r = 0.878, p < 0.001) levels of cholesterol. Children with a family history of cardiovascular disease tended to have higher values of 8-OHdG and sCD40L, but the difference was not significant. Analysis of platelet p38 MAP kinase showed that it was phosphorylated more in children with hypercholesterolemia compared with control subjects (36.8 +/- 5.8 AU vs. 8.0 +/- 4.5 AU, p < 0.001 respectively). CONCLUSIONS: Children with hypercholesterolemia have an early increase of oxidative stress that may be responsible for up-regulation of CD40L and potentially predispose to premature atherosclerosis.     

Cardiac iron overload in thalassemic patients: An endomyocardial biopsy study

Secondary heart failure induced by organ siderosis is the main cause of death in patients affected by thalassemia major. At present it cannot be predicted whether heart siderosis is correlated with iron overload and little is known about the real cardiac histological pattern of post transfusional hemochromatosis in patients with thalassemia major and intermedia. The study aim was to evaluate cardiac iron overload by non invasive and invasive techniques. Fifteen thalassemic patients were investigated and endomyocardial biopsy performed in ten revealed different grades of endomyocardial iron overload with histochemical positivity. Non invasive techniques are not able to furnish an exact picture of the cardiac hemochromatosis. There was a significant correlation between serum ferritin and myocardial iron grade.Patients with elevated ferritin levels and poor compliance to chelating therapy are at high risk of severe heart hemochromatosis. It was seen that endomyocardial biopsy is a useful tool in studying myocardial iron.     

Hepatitis C virus-related B cell subtypes in non Hodgkin's lymphoma

AIM:To evaluate if indolent B cell-non Hodgkin’s lymphoma(B-NHL) and diffuse large B-cell lymphoma(DLBCL) in hepatitis C virus(HCV) positive patients could have different biological and clinical characteristics requiring different management strategies.METHODS:A group of 24 HCV related B-NHL patients(11 indolent,13 DLBCL) in whom the biological and clinical characteristics were described and confronted.Patients with DLBCL were managed with the standard of care of treatment.Patients with indolent HCV-related B-NHL were managed with antiviral treatment pegylated interferon plus ribavirin and their course observed.The outcomes of the different approaches were compared.RESULTS:Patients with DLBCL had a shorter duration of HCV infection and a higher prevalence of HCV genotype 1 compared to patients with indolent B-NHL in which HCV genotype 2 was the more frequent genotype.Five of the 9 patients with indolent HCV-relatedB-NHL treated with only antiviral therapy,achieved a complete response of their onco-haematological disease(55%).Seven of the 13 DLBCL patients treated with immunochemotheraphy obtained a complete response(54%).CONCLUSION:HCV genotypes and duration of HCV infection differed between B-NHL subtypes.Indolent lymphomas can be managed with antiviral treatment,while DLBCL is not affected by the HCV infection.     

CX3CR1 expression defines 2 KLRG1+ mouse NK-cell subsets with distinct functional properties and positioning in the bone marrow

During development in the bone marrow (BM), NK-cell positioning within specific niches can be influenced by expression of chemokine or adhesion receptors. We previously demonstrated that the maintenance in the BM of selected NK-cell subsets is regulated by the CXCR4/CXCL12 axis. In the present study, we showed that CX3CR1 is prevalently expressed on KLRG1(+) NK cells, a subset considered terminally differentiated. Two KLRG1(+) NK-cell populations endowed with distinct homing and functional features were defined according to CX3CR1 expression. In the BM, KLRG1(+)/CX3CR1(-) NK cells were mainly positioned into parenchyma, while KLRG1(+)/CX3CR1(+) NK cells exhibited reduced CXCR4 expression and were preferentially localized in the sinusoids. We also showed that α(4) integrin plays a pivotal role in the maintenance of NK cells in the BM sinusoids and that α(4) neutralization leads to strong reduction of BM KLRG1(+)/CX3CR1(+) NK cells. Moreover, we found that KLRG1(+)/CX3CR1(+) cells originate from KLRG1(+)/CX3CR1(-) NK-cell population and display impaired capability to produce IFN-γ and to lyse YAC-1 target cells on cytokine stimulation. Altogether, our findings show that CX3CR1 represents a marker of a KLRG1(+) NK-cell population with unique properties that can irreversibly differentiate from the KLRG1(+)/CX3CR1(-) NK cells during steady state conditions.     

Laser biostimulation of cartilage: in vitro evaluation.

An in vitro study was performed to evaluate the laser biostimulation effect on cartilage using a new gallium-aluminium-arsenic diode laser. Chondrocyte cultures were derived from rabbit and human cartilage. These cells were exposed to laser treatment for 5 days, using the following parameters: 300 joules, 1 watt, 100 (treatment A) or 300 (treatment B) hertz, pulsating emission for 10 minutes, under a sterile laminar flow. Control cultures (no treatment) received the same treatment with the laser device off. Cell viability was measured by MTT assay at the end of the laser treatment and then after 5 days. Neither rabbit nor human cultured chondrocytes showed any damage under a light microscope and immunostaining control following laser treatment. The MTT test results indicated a positive biostimulation effect on cell proliferation with respect to the control group. The increase in viability of irradiated chondrocytes was maintained for five days following the end of the laser treatment. The results obtained with the Ga-Al-As diode laser using the above tested parameters for in vitro biostimulation of cartilage tissues provide a basis for a rational approach to the experimental and clinical use of this device.     

Local activation of immune response in bladder cancer patients treated with intraarterial infusion of recombinant interleukin-2

Tumor regression induced in cancer patients by i.v. infusion of interleukin-2 (IL-2) is often accompanied by severe side effects. To investigate whether local administration would affect immune response without the side effects, two 5-day cycles of continuous intraarterial [internal iliac artery] infusion of recombinant interleukin-2 (rIL-2) were performed in 12 patients with transitional cell carcinoma (tumor stage 1, node stage 0, metastasis stage 0, and grade 1-2) of the bladder. Four groups of 3 patients were treated at each of 4 escalating doses of rIL-2 (18 x 10(3), 18 x 10(4), 18 x 10(5), and 18 x 10(6) IU/m2/day) throughout the course of the two IL-2 cycles. This treatment was effective in inducing a marked intratumor inflammatory response, consisting mainly of T-lymphocytes and macrophages. A remarkable dose-dependent increase in the levels of soluble CD25 was observed in the urine of all patients, which was associated constantly with an enhanced number of intratumor CD25+ cells. Intratumor macrophages were often immunoreactive for interleukin-1 and/or tumor necrosis factor, suggesting an activated status. Increased levels of soluble CD25 and CD25+ lymphocytes were observed in peripheral blood only at the two highest doses of rIL-2, while increased percentages of circulating HLA-DR+ and CD71+ lymphoid cells and enhancement of CD3+/CD16+ T-lymphocytes were found at lower doses. Peripheral blood eosinophils were augmented in almost all patients but were rarely increased in situ. We provide evidence that continuous intraarterial infusion of rIL-2 activates host immune response, acting preferentially at the tissue level.