Bone marrow glycophorin-positive erythroid cells of myelodysplastic patients responding to high-dose rHuEPO therapy have a different gene expression pattern from those of nonresponders

The main clinical problems of low-risk patients with myelodysplastic syndromes (MDS), as defined by the International Prognostic Scoring System, are infections and the need for frequent transfusions due to ineffective myelopoiesis and peripheral blood cytopenia. Promising results in treating MDS-related anemia have been obtained using high-dose recombinant human erythropoietin (rhEPO). To evaluate the molecular basis of the response to rhEPO, we used commercially available macro-arrays to investigate gene expression profiles in the glycophorin-expressing (Gly+) bone marrow (BM) erythroid cells of five responders (ERs) and five non-responders (ENRs) to rhEPO treatment. The cells were separated by means of positive selection using an immunomagnetic procedure, after which flow cytometry showed that their purity was more than 97% in all cases. The array data were validated by means of real time RT-PCR. The results showed that the genes responsible for proliferation/differentiation and DNA repair/stability were repressed in the BM Gly+ erythroid cells of the ENRs, but almost normally expressed in the ERs. Furthermore, the expression of genes involved in signal transduction suggested that the activity of the MAPK signaling pathway is inhibited in ERs. The different gene expression profiles of ERs and ENRs may provide a basis for early gene testing as a means of predicting the response to rhEPO of MDS patients with low endogenous EPO levels.     

Verapamil 240 SR versus verapamil 120 SR in arterial hypertension. A randomized double-blind,placebo-controlled study with 24-hour ambulatory blood pressure monitoring

Summary Fifteen patients (6 males, 9 females), age range 36–70 years, were enrolled in a randomized, double-blind, placebo-controlled study according to a Latin-square design, with the aim of comparing 24-hour blood pressure profiles after three 15-day treatment periods with placebo, verapamil SR 120 mg (V120 SR) given twice daily (bid), and verapamil SR 240 mg (V240 SR) given once daily (od.) All of the patients were diagnosed as mild or moderate essential hypertensives on the basis of standard casual recordings. Noninvasive 24-hour ambulatory blood pressure (BP) monitoring was performed with an ICR Spacelab 5200 automatic device. In comparison with placebo, a clinically and statistically significant reduction in both systolic and diastolic BP over 24 hours was obtained with both active treatments. Comparison of the two active treatments shows that V240 SR led to a greater reduction in systolic and diastolic BP than V120 SR. No changes in heart rate were observed. Both treatments were well tolerated. In conclusion, both verapamil regimens proved to be effective and safe in treating essential hypertensives, with V240 SR giving better 24-hour BP control.     

Correction to: Preclinical Evaluation and Dosimetry of [111In] CHX-DTPA-scFv78-Fc Targeting Endosialin/Tumor Endothelial Marker 1 (TEM1)

Molecular Imaging and Biology - In the original article, some numerical values in the following paragraph were reported incorrectly.     

Preparation of platinum nanoparticles using iron(ii) as reductant and photosensitized H2 generation on an iron storage protein scaffold

The quest for efficient solar-to-fuel conversion has led to the development of numerous homogeneous and heterogeneous systems for photochemical stimulation of 2H⁺ + 2e⁻ → H₂. Many such systems consist of a photosensitizer, an H₂-evolving catalyst (HEC), and sacrificial electron donor often with an electron relay between photosensitizer and HEC. Colloidal platinum remains a popular HEC. We report here a novel, simple, and high yield synthesis of Pt nanoparticles (Pt NPs) associated with human heavy chain ferritin (Hfn). The formation of the Pt NPs capitalizes on Hfn''s native catalysis of autoxidation of Fe(ii)(aq) (ferroxidase activity). Fe(ii) reduces Pt(ii) to Pt(0) and the rapid ferroxidase reaction produces FeO(OH), which associates with and stabilizes the incipient Pt NPs. This Pt/Fe-Hfn efficiently catalyzes photosensitized H₂ production when combined with Eosin Y (EY) as photosensitizer and triethanolamine (TEOA) as sacrificial electron donor. With white light irradiation turnover numbers of 300H₂ per Pt, 250H₂ per EY were achieved. A quantum yield of 18% for H₂ production was obtained with 550 nm irradiation. The fluorescence emission of EY is quenched by TEOA but not by Pt/Fe-Hfn. We propose that the photosensitized H₂ production from aqueous TEOA, EY, Pt/Fe-Hfn solution occurs via a reductive quenching pathway in which both the singlet and triplet excited states of EY are reduced by TEOA to the anion radical, EY⁻˙, which in turn transfers electrons to the Pt/Fe-Hfn HEC. Hfn is known to be a remarkably versatile scaffold for incorporation and stabilization of noble metal and semiconductor nanoparticles. Since both EY and Hfn are amenable to scale-up, we envision further refinements to and applications of this photosensitized H₂-generating system.

An assembly of platinum nanoparticles produced by Fe(ii) reduction of Pt(ii) and stabilized by human heavy chain ferritin''s native catalysis of Fe(ii)(aq) autoxidation functions as an efficient photosensitized H₂ evolution catalyst.     

Evaluation of cortical thickness and bone density by roentgen microdensitometry in growing males and females

The bone mineral content (BMC) and the cortical thickness at the distal radius and at the II metacarpal were assessed in growing individuals (167 females and 158 males) by radiometric and quantitative roentgen microdensitometric methods. BMC adjusted for age and pubertal status was significantly higher in males than in females. However, the BMC corrected for bone volume (volumetric bone density, g/cm³) and the metacarpal cortical index (cortical area/total area) were identical in males and females. BMC rose progressively with age, approaching a plateau by the end of puberty. Lower but still significant increases with age were also observed for volumetric bone density of the metacarpus and the metacarpal index. These increases were also most marked by the end of pubertal maturation and might be related to diminution of bone turnover.Conclusion This study provides the normative data of bone mass in growing individuals by making use of a reasonably accurate and easily available technique. The results obtained indicate that most of the differences between males and females and the changes with age are related to changes in skeletal dimension rather than density.     

Diabetes mellitus as a contributor to the risk of acute myocardial infarction

The risk of nonfatal acute myocardial infarction (AMI) has been studied in relation to diabetes and other risk factors, combining data from three Italian case-control studies including 1,737 cases with nonfatal AMI and 2,317 controls in hospital for acute diseases unrelated to AMI risk factors. The multivariate odds ratio (OR) of AMI for diabetes was 2.3 (95% confidence interval, 1.8-2.9); the association with AMI risk was apparently stronger in patients diagnosed with diabetes when aged <40 years (OR 2.9), and in women (OR 4.4). When the combined effect of diabetes and other known risk factors on the risk of AMI was considered, compared to nondiabetic subjects with each factor at the lowest risk level, the OR for diabetic subjects was 4.7 in smokers, 2.8 in heavy coffee drinkers, 2.7 in those with higher body mass index, 3.4 in patients with high cholesterol levels, 3.3, 4.3, and 2.7 for diabetic subjects with history of hyperlipidemia, hypertension, and obesity, respectively, and 4.3 for those with a family history of AMI in first degree relatives. The association of each risk factor was much stronger in diabetic women. Preventive measures to reduce the prevalence of each additional risk factors in diabetic subjects could led to a substantial reduction of risk of AMI.     

Penetrances of breast and ovarian cancer in a large series of families tested for BRCA1/2 mutations

Accurate estimates of breast and ovarian cancer penetrance in BRCA1/2 mutation carriers are crucial in genetic counseling. Estimation is difficult because of the low frequency of mutated alleles and the often-uncertain mechanisms of family ascertainment. We estimated the penetrances of breast and ovarian cancers in carriers of BRCA1/2 mutations by maximizing the retrospective likelihood of the genetic model, given the observed test results, in 568 Italian families screened for germline mutations. The software BRCAPRO was used as a probability calculation tool in a Markov Chain Monte Carlo approach. Breast cancer penetrances were 27% (95% CI 20-34%) at age 50 years and 39% (27-52%) at age 70 in BRCA1 carriers, and 26% (0.18-0.34%) at age 50 and 44% (29-58%) at age 70 in BRCA2 carriers, and ovarian cancer penetrances were 14% (7-22%) at age 50 and 43% (21-66%) at age 70 in BRCA1 carriers and 3% (0-7%) at age 50 and 15% (4-26%) at age 70 in BRCA2 carriers. The new model gave a better fit than the current default in BRCAPRO, the likelihood being 70 log units greater; in addition, the observed numbers of mutations in families stratified by gene and by cancer profile were not significantly different from those expected. Our new penetrance functions are appropriate for predicting breast cancer risk, and for determining the probability of carrying BRCA1/2 mutations, in people who are presently referred to genetic counseling in Italy. Our approach could lead to country-customized versions of the BRCAPRO software by providing appropriate population-specific estimates.