Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning.

The glycosyltransferase gene, Ext1, is essential for heparan sulfate production. Induced deletion of Ext1 selectively in Mx1-expressing bone marrow (BM) stromal cells, a known population of skeletal stem/progenitor cells, in adult mice resulted in marked changes in hematopoietic stem and progenitor cell (HSPC) localization. HSPC egressed from BM to spleen after Ext1 deletion. This was associated with altered signaling in the stromal cells and with reduced vascular cell adhesion molecule 1 production by them. Further, pharmacologic inhibition of heparan sulfate mobilized qualitatively more potent and quantitatively more HSPC from the BM than granulocyte colony-stimulating factor alone, including in a setting of granulocyte colony-stimulating factor resistance. The reduced presence of endogenous HSPC after Ext1 deletion was associated with engraftment of transfused HSPC without any toxic conditioning of the host. Therefore, inhibiting heparan sulfate production may provide a means for avoiding the toxicities of radiation or chemotherapy in HSPC transplantation for nonmalignant conditions.

Flow-mediated dilatation assessment in women with preeclampsia compared to women with gestational hypertension.

OBJECTIVES: To assess flow-mediated dilatation (FMD) in women with preeclampsia (PE) versus gestational hypertension (GH) and to determine if results of this ultrasound method vary with modifications to the technique. METHODS: Pregnant women with hypertension (BP ≥ 140/90 mmHg) were recruited. Women were allocated to the PE group if they had proteinuria ≥300 mg/24 h. FMD(o) was calculated from the percentage difference in baseline and post-occlusion (PO) diameter at 45-60 s and FMD(max) from baseline and maximum diameter between 45 and 90 s. FMD(max) was adjusted for hematocrit and shear rate. RESULTS: FMD(o) (m ± SD) was similar (p = 0.83) in the no medication GH (5.3 ± 3.2; n = 15) and the PE (6.5 ± 4.1; n = 13) groups. FMD(o) was reduced (p < 0.001) in the medication GH (3.7 ± 2.8; n = 23) versus the PE (8.8 ± 4.3; n = 25) groups. For FMD(max) the interaction between group and medication was not significant (both p = 0.08) in unadjusted analysis or analysis adjusted for covariates hematocrit (p = 0.023) and shear rate (p = 0.007). Means averaged over medication are presented. FMD(max) was reduced (p < 0.0001) in the GH (5.7 ± 4.0; n = 38) versus the PE group (9.2 ± 4.0; n = 38). Of the PE women, 79% (30/38) reached maximum dilatation by 90 s compared with 63% (24/38) of the GH women (chi-square, p = 0.16). CONCLUSIONS: The FMD(max) analysis revealed reduced FMD in GH women compared with PE women. We therefore hypothesize that PE may be a different disease to GH. Our work demonstrates differing results in FMD(o) and FMD(max) because of modifications in the technique. Previous work on PE and FMD may not be definitive due to this evolving technique.

Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation.

Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including IL-6, stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6-induced hepcidin expression, an effect that was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists noggin and ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189. In mice, treatment with IL-6 or turpentine increased hepcidin expression and reduced serum iron, effects that were inhibited by LDN-193189 or ALK3-Fc. Chronic turpentine treatment led to microcytic anemia, which was prevented by concurrent administration of LDN-193189 or attenuated when LDN-193189 was administered after anemia was established. Our studies support the concept that BMP and IL-6 act together to regulate iron homeostasis and suggest that inhibition of BMP signaling may be an effective strategy for the treatment of anemia of inflammation.

A longitudinal study using ultrasound to assess flow-mediated dilatation in normal human pregnancy.

OBJECTIVE: To develop normal ranges of endothelial function in normal human pregnancy to use as a screening test for preeclampsia. METHODS: In this longitudinal study, women were studied five times during pregnancy and once postpartum using flow-mediated dilatation (FMD). FMD is a noninvasive ultrasound technique used to assess endothelial function. Healthy nonpregnant women were controls. RESULTS: FMD increased non-significantly in pregnancy until 32 weeks, when it decreased significantly at 36+ weeks (n = 47). CONCLUSION: The fall in FMD in the third trimester has not been previously reported. This indicates the importance of gestational age when assessing FMD as a screening test for preeclampsia.

Survey of the management of preterm labour in Australia and New Zealand in 2002.

AIM: To determine current attitudes and practices regarding the suppression of preterm labour among obstetricians in Australia and New Zealand. METHODS: A questionnaire mailed to all Diplomates, Members and Fellows of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists in April 2002. RESULTS: A total of 813 surveys were returned - 33% (470/1412) of Fellows and Members and 11% (322/2806) of Diplomates. The response rate for Australia was 18.9% (759 of 4019) compared to 27.1% (54 of 199) from New Zealand. Routine suppression of preterm labour was attempted by 79% of respondents, primarily to prolong pregnancy for steroid administration (83%) and/or transfer (74%). The gestation for initiation of suppression ranged from 20 to 37 weeks. Tocolysis was discontinued at 32.9 +/- 2.7 weeks (mean +/- SD), range 24-38 weeks. The first choice drug for tocolysis was the beta-adrenergic group (73%), followed by nifedipine (21%). Maintenance tocolysis was used by 34%. Respondents were asked the percentage of women in whom suppression was attempted that achieved: (i) steroid cover--median 80% (range 10-100); (ii) prolongation of pregnancy > or =7 days--50% (0-100); and (iii) prolongation of pregnancy to term--10% (0-100). CONCLUSION: Most respondents attempted to suppress preterm labour for steroid administration and/or transfer. However, a wide range of opinions and uncertainty was evident as to the effectiveness of tocolytic therapy in clinical management, the most appropriate drug and drug side-effects.