No abstract

Bone mass and bone turnover are under genetic control. Restriction fragment length polymorphisms (RFLPs) at the vitamin D receptor (VDR) gene locus have been recently correlated to bone mineral density (BMD) and rate of bone loss. However, agreement on this relationship is not universal. The existence of ethnical and environmental differences between populations, a health-based selection bias in several previous studies, and the involvement of other genes could explain these discordant findings. In this study, we examined the relationship of VDR and estrogen receptor (ER) gene RFLPs with lumbar spine and upper femur BMD in 426 Italian postmenopausal women, 57.7 +/- 0.4 yr old (144 normal, 106 osteopenic, and 176 osteoporotic). VDR gene RFLPs for ApaI, Bsm I, and TaqI restriction endonucleases and ER RFLPs for PvuII and XbaI restriction endonucleases were assessed by Southern blotting analysis and were indicated, respectively, as A-a, B-b, T-t, P-p, and X-x (uppercase letters signifying the absence and lowercase letters the presence of the restriction site). After correcting for potential confounding factors (age, height, weight, age since menopause, osteophytosis, and facet joint osteoarthritis), a statistically significant VDR genotype effect on lumbar BMD (P = 0.01, analysis of covariance), but not on femoral BMD, was detected, with subjects in AABBtt genotype showing a 13% lower BMD than those with aabbTT genotype (P < 0.05, Tukey's test). Moreover, a statistically significant prevalence of AABBtt genotype in osteoporotics, and of AabbTT and aabbTT genotypes in nonosteoporotics, were detected. Conversely, there was no significant relationship of ER genotype to either lumbar or femoral BMD, even though a trend for higher BMD values in women with the ER PP genotype (with respect to those with ER pp genotype) was detected. When mean lumbar BMD was calculated for women grouped by ER and VDR genotype, we observed a significant difference between those within the 2 opposite associations AABBtt-PPXX and aabbTT-ppxx (0.71 +/- 0.05 vs. 0.97 +/- 0.03 g/cm2, P < 0.05 Tukey's test). These results are consistent with a segregation of the VDR AABBtt genotype with a higher risk of developing osteoporosis, in the Italian female population. The introduction of another variable, the ER genotype, in the analysis of VDR genetic determination of BMD, may represent a useful model in the identification of patients at risk of developing a multigenic disorder like osteoporosis.

Summary. Treatment with recombinant human erythropoietin (rhEPO) improves anaemia in < 20% of the patients with myelodysplastic syndromes (MDS). Recent reports suggest that a combination treatment with rhEPO plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) given for up to 18 weeks may result in a higher erythroid response rate than with rhEPO alone. We investigated the potential advantage of an even more prolonged schedule of combined rhG-CSF and rhEPO treatment to obtain and maintain stable responses. In a phase II study, 33 patients with MDS [17 with refractory anaemia (RA), eight with RA with ringed sideroblasts (RARS), eight with RA with excess blasts (RAEB) with bone marrow blast counts less than 20%] were scheduled to receive at least 36 weeks of combined therapy with rhG-CSF and rhEPO. Seventeen of 28 evaluable patients demonstrated an erythroid response [61%; 95% confidence interval (CI) 41±78] after 12 weeks of treatment. The erythroid response rate was 80% (20 of 25 evaluable patients; 95% CI 59±93) after 36 weeks. Seven of these responses developed between week 12 and week 36, whereas two initially responding patients became refractory. The cytokine therapy was generally well tolerated. Nineteen of the 20 patients responding after 36 weeks continued to be treated with both cytokines. After 1 year and 2 years of continuous combined treatment, 50% of the initially included patients showed a continuing response. Our results suggest that a prolonged combination treatment with rhG-CSF and rhEPO is highly effective in achieving a stable and long-lasting erythroid response in many patients with MDS and low blast count.

Our data suggest that sperm wash and ICSI could be useful for reducing the risk of HIV and/or HCV transmission in serodiscordant couples with infected male wishing to have a child, irrespective of their fertility status.

Reactivation of fetal hemoglobin synthesis in adulthood can be seen in hematological disorders affecting the erythropoietic system. The objective of the present study was to evaluate the incidence and prognostic significance of increased hemoglobin F in patients with myelodysplastic syndrome. Hemoglobin F concentrations and Ggamma/Ggamma + A gamma-globin chain ratios were determined in 26 patients with primary myelodysplastic syndrome. Median age of the patients was 65 years; all FAB subtypes were included. Increased hemoglobin F concentration of up to 20% of total hemoglobin (normal: below 2%) was seen in 16 patients; ten patients had normal values. There was a significant relation between hemoglobin F concentration and the course of disease, e.g., 12 of the 16 patients with elevated hemoglobin F survived at least 1 year after the examination, in contrast to only three of the ten patients with normal hemoglobin F (p < 0.025). All of six patients with hemoglobin F above 5% survived at least 1 year. There was no significant difference in the hemoglobin F concentration between patients with and without cytogenetic anomalies. The Ggamma/Ggamma + A gamma-globin chain ratio was slightly elevated in all patients, with a weak correlation to the degree of hemoglobin F elevation. The values were not of additional prognostic significance. The data of the present study suggest that the hemoglobin F concentration may be a prognostic parameter in myelodysplastic syndrome; increased hemoglobin F concentration may indicate a better prognosis.