Doron Kreiser

CD133‐Positive Hematopoietic Stem Cell “Stemness” Genes Contain Many Genes Mutated or Abnormally Expressed in Leukemia

Affymetrix human Hu133A oligonucleotide arrays were used to study the expression profile of CD133+ cord blood (CB) and peripheral blood (PB) using CD133 cell‐surface marker. An unsupervised hierarchical clustering of 14,025 valid probe sets showed a clear distinction between the CD133+ cells representing the hematopoietic stem cell (HSC) population and CD133‐differentiated cells. Two hundred forty‐four genes were found to be upregulated by at least twofold in the CD133‐positive cells of both CB and PB compared with the CD133‐negative cells. These genes represent the hematopoietic “stemness,” whereas the 218 and 304 upregulated genes exclusively in PB and CB, respectively, represent tissue specificity. Some of the stemness genes were also common to HSC genes found to be upregulated in several recently published studies. Among these common stemness genes, we identified several groups of genes that have an important role in hematopoiesis: growth factor receptors, transcription factors, genes that have an important role in development, and genes involved in cell growth. Sixteen selected stemness genes are known to be mutated or abnormally regulated in acute leukemias. It can be suggested that key hematopoietic stemness machinery genes may lead to abnormal proliferation and leukemia upon mutation or change of their expression.

End tidal carbon monoxide levels are lower in women with gestational hypertension and pre-eclampsia.

BACKGROUND: The possible role of heme oxygenase and its byproduct carbon monoxide (CO) in the regulation of blood pressure is under investigation. The aim of this study was to compare end tidal breath CO (ETCO) levels in women with gestational hypertension (GH) or pre-eclampsia to the levels in healthy pregnant and nonpregnant women.MATERIALS AND METHODS: We prospectively performed ETCO measurements corrected for ambient CO (ETCOc) in two medical centers (Stanford, CA and Cleveland, OH). A Natus® CO-Stat® End Tidal Breath Analyzer (Natus Medical Inc., San Carlos, CA) was used. The study group included a convenience sample of 31 women with GH/pre-eclampsia (PE). Control groups included 46 nonpregnant healthy women, 44 first-trimester and 48 third-trimester pregnant healthy women.RESULTS: Mean±SD ETCOc measurements were significantly lower in the GH/PE group compared to first-trimester (p=0.004) and third-trimester (p=0.001) normotensive pregnant and nonpregnant women (p=0.002) (1.36±0.30 vs 1.76±0.47, 1.72±0.42 and 1.78±0.54 ppm, respectively). The ETCOc values were ≤1.6 ppm in 89% of GH/PE women compared with, respectively, only 45, 54, and 46% of nonpregnant, first- and third-trimester normotensive pregnant women (p<0.05). ETCO measurements were not influenced by maternal age, parity, ethnicity, body mass index, gestational age or presence of household smokers. In the two centers, the controls had a similar mean ETCOc and the differences found remained significant when results for each center were analyzed separately.CONCLUSIONS: ETCOc levels were found to be significantly lower in women with GH/PE. Further investigation is required to determine if the lower CO levels reflect a deficient compensatory response to the increase in blood pressure or whether these are primary changes of significance to our understanding of the pathogenesis of GH/PE.

Heme oxygenase-1 modulates fetal growth in the rat

Intrauterine growth restriction is associated with increased perinatal morbidity and mortality as well as with lifelong cardiovascular and metabolic complications. Deficiency of heme oxygenase 1 (HO-1) is associated with growth restriction in mice and in humans, suggesting a role for HO-1 in fetal growth and maintenance of pregnancy. We hypothesized that modulation of HO-1 in the pregnant rat would alter fetal growth. In pregnant dams, placental HO activity was significantly inhibited with zinc deuteroporphyrin IX 2,4 bis glycol, and HO-1 protein was increased by transducing adenoviral human HO-1. Inhibition of HO-1 by zinc deuteroporphyrin IX 2,4 bis glycol resulted in a significant decrease in pup size, whereas transfection with hHO-1 resulted in increased pup size. Furthermore, the expression of IGF binding protein-1 and its receptor paralleled the expression of HO-1 in the placenta and were significantly modulated by modification of HO-1 along with the expression of vascular endothelial growth factor. These observations demonstrate that HO-1 modulates fetal growth by its effects on placental growth factors.

The effect of ephedrine on intrapartum fetal heart rate after epidural analgesia.

OBJECTIVE: Adverse fetal heart rate (FHR) changes occur frequently during the first 30 minutes after epidural analgesia. The aim of this study was to estimate whether intravenous administration of ephedrine during induction of epidural analgesia can reduce the frequency of adverse FHR changes. METHODS: We prospectively studied 145 term singleton deliveries where epidural analgesia was administered. The patients were randomly allocated before the administration of epidural analgesia to receive an intravenous infusion of 10 mg ephedrine, after epidural induction, followed by a continuous infusion for 60 minutes of 20 mg ephedrine (study group) or to receive no ephedrine (control group). The FHR tracing was evaluated for 20 minutes before and 40 minutes after initiating epidural analgesia. Demographic data and clinical and delivery outcome were assessed and compared between the 2 groups. RESULTS: Injection of ephedrine significantly reduced the rate of major FHR changes appearing 15–25 minutes after induction of epidural analgesia in the study group compared with the control group (2/72 compared with 11/73, respectively; P = .009). To avoid 1 case of adverse FHR changes, 6.8 women should be treated with ephedrine. Maternal and fetal characteristics and outcome and mode of delivery were similar in the 2 groups. Mean arterial pressure was significantly higher in the study group from the time of analgesia induction and during the subsequent 25 minutes. Maternal heart rate was transiently reduced in the study group only. CONCLUSION: Ephedrine administration during the time of epidural analgesia initiation can reduce the frequency of adverse FHR changes commonly observed immediately afterward. LEVEL OF EVIDENCE: I

Gestational Pattern of Heme Oxygenase Expression in the Rat

Fetal growth is influenced by many intrinsic and extrinsic factors. Our objective was to determine the pattern of heme oxygenase (HO) expression in the pregnant rat and to study its association with fetal growth and growth factors. Uterine tissues were obtained from nonpregnant and from time-mated rats at 7, 13, 16, 19, and 21 d of pregnancy. Placental tissue was obtained on d 13, 16, 19 and 21 of pregnancy. Tissues were evaluated for HO activity, HO-1, HO-2, leptin and vascular endothelial growth factor protein, and HO-1 and HO-2 mRNA. HO activity in both the uterus and placenta peaked on d 21 of pregnancy. In the uterus, HO-1 and HO-2 protein and total mRNA levels peaked on d 16 of pregnancy, whereas, in the placenta, HO-1 and HO-2 protein levels peaked on d 19. Additionally, placental HO-1 mRNA peaked on d 16, but placental HO-2 mRNA declined toward the end of pregnancy. Placental leptin and vascular endothelial growth factor protein levels followed a similar pattern to placental HO-1 and peaked on d 16. We conclude that there is a clear uterine and placental gestational pattern of HO expression in the rat. This pattern is comparable to that of vascular endothelial growth factor and leptin.

Unrelated and related cord blood banking and hematopoietic graft engineering

The first successful transplantation of umbilical-cord blood (CB) was performed in 1988 to treat a boy with Fanconis anemia, using CB from his HLA full-matched sister. A few years later, CB transplantation (CBT) was also performed in an adult recipient, however major obstacles still prevent a wider application of CBT in this age group. The principle limiting-factor is the low numbers of nucleated (NC) and CD34+ cells available for transplantation compared to a typical bone marrow (BM)/peripheral blood (PB) allograft, resulting in a lower engraftment success as well as delayed hematopoietic recovery with its characteristic complications, including infections and transplant related mortality (TRM). Other problems include uncertainty regarding potency and efficacy of graft versus leukemia (GvL)/tumor effects in this kind of transplant, considering the reduced graft versus host disease (GvHD) manifestations and immunologic prematurity. These subjects are reviewed with orientation to technical methods directed to improve CB grafts and graft engineering.

End-tidal Breath Carbon Monoxide Measurements are Lower in Pregnant Women with Uterine Contractions

OBJECTIVE: To compare the levels of end-tidal carbon monoxide (ETCOc) among women with and without uterine contractions in term and preterm pregnancies.STUDY DESIGN: In all, 55 nonsmoking healthy pregnant women were enrolled. ETCOc levels were compared among women with contractions (10 preterm and 13 term) and 32 women without contractions (34–41 weeks gestation).RESULTS: Maternal age, gravidity and parity were similar among study and control groups. ETCOc levels were significantly lower among women that had uterine contractions (0.99±0.38 parts per million (ppm) and 1.15±0.34 p.p.m. respectively), compared to women with no contractions (1.70±0.52 p.p.m., P<0.002). However, there was no significant difference in the ETCOc levels between women with preterm or term contractions (P=0.48).CONCLUSIONS: Low levels of ETCOc are associated with preterm and term uterine contractions.