Splenomegaly is common in beta-thalassemia, bearing some particular hemodynamic features, while splenectomy is an established therapeutic intervention in these patients. Their effects, however, on systemic hemodynamics and thalassemia heart disease have not yet been assessed. The study included 32 consecutive patients, 13 with thalassemia major (TM) and 19 with thalassemia intermedia (TI), aged 23.4+/-4.2 years, requiring splenectomy. Assessment was performed before and 6 months after splenectomy and included hematological profile and resting echocardiography; total blood volume was also measured in 10 of 32 cases. Preoperative echocardiographic data were compared with those of 34 controls. Preoperative left ventricular diameters and mass, cardiac index, and systolic pulmonary artery pressure were all significantly higher in patients compared to controls (p<0.001), but did not differ significantly between TM and TI patients. Postoperatively, the mean hemoglobin level increased from 8.1+/-0.6 to 9.1+/-0.4 g/dl (p<0.001), total blood volume index declined from 2847+/-332 to 2310+/-276 ml/m(2) (p<0.001), blood transfusions were discontinued in 80% of TI patients and mean 6-monthly transfusion requirements in TM patients were reduced from 28+/-5 to 22+/-4 units (p<0.001). However, cardiac parameters were not significantly modified. It seems that left ventricular remodeling, high output state, and increased pulmonary artery pressure characterize both TM and TI patients who require splenectomy. Although these abnormalities remain unchanged after splenectomy, the removal of the spleen may contribute to the prevention of further cardiac damage by ameliorating the patients' hematological status and reducing their transfusion needs.

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Background: Plasma B-type natriuretic peptide (BNP) concentration has significant diagnostic accuracy and prognostic value in various forms of heart disease. Whether BNP is also useful in the evaluation and management of thalassaemia heart disease remains to be determined. Methods and results: Eighty three thalassaemia major patients; 8 with acutely decompensated heart failure (New York Heart Association [NYHA] class III or IV, group A), 25 with NYHA class II symptoms and impaired systolic left ventricular function (ejection fraction b 55% or fractional shortening b 30%, group B) and 50 with normal systolic function (group C), as well as 50 healthy controls, were studied. Assessment included history, physical examination, Doppler echocardiography and plasma BNP determination. Mean BNP levels were 431 ± 219 pg/mL (range, 283-890 pg/mL) in group A, 158 ± 31 pg/mL in group B, 176 ± 54 pg/mL in group C and 43 ± 24 pg/mL in controls. BNP levels were significantly higher in group A ( p b 0.001), but did not differ between groups B and C. Moreover, BNP was not correlated with left ventricular end-diastolic diameter, left ventricular mass, right ventricular diameter index, Doppler diastolic indexes (except in group C), the mean 2-year serum ferritin concentration or the peak serum ferritin concentration in any of the three patient groups. Conclusion: A potential deficiency of BNP-related neurohormonal mechanisms may impair its clinical usefulness in thalassaemia major.

Conjugated lactam-steroid alkylators (LSA) have been shown to exhibit superior activity at controlling cancer models and overlap drug resistance to conventional chemjournalapy. Hybrid LSA combine two active compounds in a single molecule and incorporate modified steroids bearing lactam moiety in one or more steroid rings functioning as vectors for cytotoxic agents. We first describe a novel class of LSA that generate excellent anticancer activity against UWB1.289 and UWB1.289 + BRCA1 human ovarian cancer cell lines. Both UWB1.289 and UWB1.289 + BRCA1 cells carry mutations in the tumor suppressor gene TP53 while UWB1.289 cell line carries a germline BRCA1 mutation. In vitro, in vivo, and in silico, experimental methods were utilized to determine the poly(ADP-ribose) polymerases (PARPs) activity and mRNA transcription, DNA damage, cytostatic and cytotoxic effects, and virtual molecular interactions, in order to study the molecular mechanisms of activity of the tested LSA. LSA produce anticancer activity through dual action by combining the direct induction of cellular DNA damage with the inhibition of PARP activity and consecutive DNA repair activity. BRCA1-mutated UWB1.289 ovarian cancer cells with defective PARP-oriented repair mechanism show significantly higher sensitivity to these agents. Combined drug effect on DNA damage and repair is a novel approach in cancer therapeutics.