The hematopoietic stem cells of alpha-thalassemic mice

The alpha-thalassemic mouse has a hereditary microcytic anemia, almost certainly has a shortened RBC life span, and is a potential candidate for cell replacement therapy. In a routine study of bone marrow repopulating capacity using hemoglobin as a cell marker, normal donor marrow cells, but not alpha-thalassemic donor marrow cells, completely replaced the host cells. Further analysis showed that at least 30 times more alpha-thalassemic cells were required to outcompete normal donor cells injected simultaneously. The results were more extreme then expected and suggested a defect in a stem cell population as well as in the RBCs. Evidence that the multipotent and erythroid-committed stem cells in alpha-thalassemic mice are not decreased was shown by CFU-S and CFU-E assays. The combined results indicate that the deletion expresses itself most conspicuously in the RBC population. Tests were also performed to analyze repopulation kinetics in the Hbath-J/+ mice. In unirradiated alpha-thalassemic hosts, the hemoglobin from a normal donor persisted but did not replace the host hemoglobin. Sublethally irradiated alpha-thalassemic hosts, on the other hand, were easily repopulated with normal cells. We conclude that the alpha-thalassemic mouse is a good model for cell replacement therapy.     

Autoregulation of Cerebral Blood Flow in Fetuses with Congenital Heart Disease: The Brain Sparing Effect

Fetuses with congenital heart disease (CHD) have circulatory abnormalities that may compromise cerebral oxygen delivery. We believe that some CHD fetuses with decreased cerebral oxygen supply have autoregulation of blood flow that enhances cerebral perfusion (brain sparing). We hypothesize that cerebral autoregulation occurs in CHD fetuses, and the degree of autoregulation is dependent on the specific CHD and correlates with intrauterine head circumferences. CHD fetuses were compared to normal fetuses. Data included cardiac diagnosis, cerebral and umbilical artery Doppler, head circumference, weight, and gestational age. The cerebral-to-placental resistance ratio (CPR) was assessed as a measure of cerebral autoregulation. CPR = cerebral/umbilical resistance index (RI) and RI = systolic–diastolic/systolic velocity (normal CPR>1). CPR>1 was found in 95% of normal vs 44% of CHD fetuses. The incidence of CPR<1 was greatest in hypoplastic left or right heart fetuses. Compared to normal, cerebral RI was decreased in CHD fetuses. The CPR vs gestational age relationship, and the relationship among weight, head circumference, and CPR differed across normal and CHD fetuses. Fetuses > 2 kg with CHD and a CPR<1 had smaller head circumferences than normal. Brain sparing occurs in CHD fetuses. Fetuses with single ventricular physiology are most affected. Inadequate cerebral flow in CHD fetuses, despite autoregulation, may alter brain growth.     

A longitudinal study of otitis media with effusion among 2- to 5-year-old African-American children in child care

OBJECTIVE: To prospectively document the prevalence of otitis media with effusion (OME) in 86 African-American children between ages 2 and 5 years. STUDY DESIGN: Eighty-six children in center-based child care whose ear status had been followed from infancy continued to be observed. Middle ear status was assessed by pneumatic otoscopy and tympanometry biweekly. RESULTS: The prevalence of OME decreased as children became older. The mean proportion of examinations demonstrating bilateral OME (BOME) ranged from 12% between 24 to 30 months to 4% between 54 to 60 months of age. The mean proportion of exams revealing bilateral normal ears increased from 77% at 24 to 30 months to 88% at 54 to 60 months of age. Although 60 children had experienced BOME that lasted 4 months or longer in the 6- to 24-month age period, only 8 of these children experienced at least 4 months of continuous BOME between 24 to 60 months. CONCLUSIONS: The proportion of time with BOME decreased progressively with increasing age in this population. Only 8 of 60 children who had experienced more than 4 consecutive months of BOME before 2 years of age continued to manifest persistent effusion or experience recurrences of prolonged BOME after 2 years of age.     

<Emphasis Type="Italic">TCF7L2</Emphasis>variant genotypes and type 2 diabetes risk in Brazil: significant association,but not a significant tool for risk stratification in the general population

Background  

Genetic polymorphisms of the TCF7L2 gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide. In this study, we aimed to confirm the effect of the TCF7L2 polymorphism rs7903146 on diabetes risk in a Brazilian population and to assess the use of this genetic marker in improving diabetes risk prediction in the general population.     

Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: In vivo neovascularization induced by stromal-derived factor-1alpha

The contribution of chemokines toward angiogenesis is currently a focus of intensive investigation. Certain members of the CXC chemokine family can induce bovine capillary endothelial cell migration in vitro and corneal angiogenesis in vivo, and apparently act via binding to their receptors CXCR1 and CXCR2. We used an RNAse protection assay that permitted the simultaneous detection of mRNA for various CXC chemokine receptors in resting human umbilical vein endothelial cells (HUVECs) and detected low levels of only CXCR4 mRNA. Stimulation of HUVECs with vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) up-regulated levels of only CXCR4 mRNA. CXCR4 specifically binds the chemokine stromal-derived factor-1alpha (SDF-1alpha). Competitive binding studies using 125I-labeled SDF-1alpha with Scatchard analysis indicated that VEGF or bFGF induced an average number of approximately 16,600 CXCR4 molecules per endothelial cell, with a Kd = 1.23 x 10(-9) mol/L. These receptors were functional as HUVECs and human aorta endothelial cells (HAECs) migrated toward SDF-1alpha. Although SDF-1alpha-induced chemotaxis was inhibited by the addition of a neutralizing monoclonal CXCR4 antibody, endothelial chemotaxis toward VEGF was not altered; therefore, the angiogenic effect of VEGF is independent of SDF-1alpha. Furthermore, subcutaneous SDF-1alpha injections into mice induced formation of local small blood vessels that was accompanied by leukocytic infiltrates. To test whether these effects were dependent on circulating leukocytes, we successfully obtained SDF-1alpha-induced neovascularization from cross sections of leukocyte-free rat aorta. Taken together, our data indicate that SDF-1alpha acts as a potent chemoattractant for endothelial cells of different origins bearing CXCR4 and is a participant in angiogenesis that is regulated at the receptor level by VEGF and bFGF.     

Copy number variants in patients with short stature

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents'' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.     

Nationwide Implementation of Hello World: A Dutch Email-Based Health Promotion Program for Pregnant Women

Background

In November 2006, an email-based health promotion program for pregnant women was implemented nationally in the Netherlands. The program consisted of emails containing quizzes with pregnancy-related questions tailored to the number of weeks of pregnancy. Emails were sent out once every 4 weeks, up to a maximum of nine emails.

Objectives

The aims of the study were (1) to assess the recruitment of participants and their representativeness of the Dutch population and (2) to study differences in recruitment, program use, and program appreciation among women with different levels of education.

Methods

Data from 13,946 pregnant women who enrolled during the first year of the program were included. Upon registration, participants were asked how they found out about the program and subsequently received an email questionnaire to assess demographic, lifestyle, and Internet characteristics. Program use was tracked, and participants were classified into five user groups (inactive to very active). Program appreciation (low, intermediate, and high) was assessed twice with an email questionnaire that was sent after the woman had received her third and sixth quiz email. Information about pregnant women and their characteristics was obtained from Dutch registries to assess representativeness of the study population.

Results

About 8% of the pregnant women in the Netherlands enrolled in the program. Immigrants were underrepresented, and women with a low level of education seemed to be slightly underrepresented. Most women knew about the program from a promotional email sent by the organization (32%), followed by the Internet (22%) and midwives (16%). Women with little education were more often inactive users of the program than were highly educated women (15% vs 11%, P < .001), whereas highly educated women were more often very active users compared with women with little education (25% vs 20%, P< .001). However, women with less education were more likely than women with more education to have a high appreciation of the program after receiving three quiz emails (52% vs 44%, P = .001).

Conclusions

In this real-life setting, pregnant women can be reached through an email-based health promotion program. Selective engagement by education level remains a challenge.