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2.  Hypoxia Promotes Osteogenesis but Suppresses Adipogenesis of Human Mesenchymal Stromal Cells in a Hypoxia-Inducible Factor-1 Dependent Manner 
PLoS ONE  2012;7(9):e46483.
Bone fracture initiates a series of cellular and molecular events including the expression of hypoxia-inducible factor (HIF)-1. HIF-1 is known to facilitate recruitment and differentiation of multipotent human mesenchymal stromal cells (hMSC). Therefore, we analyzed the impact of hypoxia and HIF-1 on the competitive differentiation potential of hMSCs towards adipogenic and osteogenic lineages.
Methodology/Principal Findings
Bone marrow derived primary hMSCs cultured for 2 weeks either under normoxic (app. 18% O2) or hypoxic (less than 2% O2) conditions were analyzed for the expression of MSC surface markers and for expression of the genes HIF1A, VEGFA, LDHA, PGK1, and GLUT1. Using conditioned medium, adipogenic or osteogenic differentiation as verified by Oil-Red-O or von-Kossa staining was induced in hMSCs under either normoxic or hypoxic conditions. The expression of HIF1A and VEGFA was measured by qPCR. A knockdown of HIF-1α by lentiviral transduction was performed, and the ability of the transduced hMSCs to differentiate into adipogenic and osteogenic lineages was analyzed. Hypoxia induced HIF-1α and HIF-1 target gene expression, but did not alter MSC phenotype or surface marker expression. Hypoxia (i) suppressed adipogenesis and associated HIF1A and PPARG gene expression in hMSCs and (ii) enhanced osteogenesis and associated HIF1A and RUNX2 gene expression. shRNA-mediated knockdown of HIF-1α enhanced adipogenesis under both normoxia and hypoxia, and suppressed hypoxia-induced osteogenesis.
Hypoxia promotes osteogenesis but suppresses adipogenesis of human MSCs in a competitive and HIF-1-dependent manner. We therefore conclude that the effects of hypoxia are crucial for effective bone healing, which may potentially lead to the development of novel therapeutic approaches.
PMCID: PMC3459928  PMID: 23029528
4.  What Do We Need beyond Hemoglobin A1c to Get the Complete Picture of Glycemia in People with Diabetes? 
Hemoglobin A1c (HbA1c) is currently the most commonly used marker for the determination of the glycemic status in people with diabetes and it is frequently used to guide therapy and especially medical treatment of people with diabetes. The measurement of HbA1c has reached a high level of analytical quality and, therefore, this biomarker is currently also suggested to be used for the diagnosis of diabetes. Nevertheless, it is crucial for people with diabetes and their treating physicians to be aware of possible interferences during its measurement as well as physiological or pathological factors that contribute to the HbA1c concentration without being related to glycemia, which are discussed in this review. We performed a comprehensive review of the literature based on PubMed searches on HbA1c in the treatment and diagnosis of diabetes including its most relevant limitations, glycemic variability and self-monitoring of blood glucose (SMBG). Although the high analytical quality of the HbA1c test is widely acknowledged, the clinical relevance of this marker regarding risk reduction of cardiovascular morbidity and mortality is still under debate. In this respect, we argue that glycemic variability as a further risk factor should deserve more attention in the treatment of diabetes.
PMCID: PMC3465850  PMID: 23055818
Hemoglobin A1C; diabetes mellitus; hemoglobinopathies; glycemic control; glycemic variability; diabetes complications.
5.  Early Exclusive Breastfeeding and Maternal Attitudes Towards Infant Feeding in a Population of New Mothers in San Francisco, California 
Breastfeeding Medicine  2010;5(1):9-15.
Positive parental attitudes towards infant feeding are an important component in child nutritional health. Previous studies have found that participants in the Special Supplemental Women, Infants, and Children (WIC) Program have lower breastfeeding rates and attitudes that do not contribute towards healthy infant feeding in spite of breastfeeding and nutrition education programs targeting WIC participants. The objective of this study was to assess the frequency of exclusive breastfeeding in the early postpartum period and maternal attitudes towards breastfeeding in a population of mothers at two San Francisco hospitals and in relation to WIC participation status.
We interviewed women who had recently delivered a healthy newborn using a structured interview.
A high percentage (79.8%) of our sample was exclusively breastfeeding at 1–4 days postpartum. We did not find any significant differences in rates of formula or mixed feeding by WIC participant status. Independent risk factors for mixed or formula feeding at 1–3 days postpartum included Asian/Pacific Islander ethnicity (odds ratio [OR] 2.90, 95% confidence interval [CI] 1.17–7.19). Being a college graduate was associated with a decreased risk of formula/mixed feeding (OR 0.28, 95% CI 0.10–0.79). We also found that thinking breastfeeding was physically painful and uncomfortable was independently associated with not breastfeeding (OR 1.41, 95% CI 1.06–1.89).
Future studies should be conducted with Asian-Americans and Pacific Islanders to better understand the lower rates of exclusive breastfeeding in this population and should address negative attitudes towards breastfeeding such as the idea that breastfeeding is painful or uncomfortable.
PMCID: PMC2936253  PMID: 19772374
6.  A Clinic-Based Lifestyle Intervention for Pediatric Obesity: Efficacy and Behavioral and Biochemical Predictors of Response 
To examine efficacy and predictors of response to a lifestyle intervention for obese youth.
Retrospective chart review of 214 children and adolescents aged 8-19 years. Linear regression identified baseline predictors of response (Δ BMI z-score) at first and ultimate follow-up visits.
Mean Δ BMI z-score from baseline was -0.04 (p <0.001) at first follow-up and -0.09 (p <0.001) at ultimate follow-up (median time 10 mo) among 156 children and adolescents. Higher baseline BMI z-score predicted poor response at first and ultimate follow-up, explaining 10% of variance in response. Fasting insulin explained 6% of response variance at first follow-up. Δ BMI z-score at the first visit along with baseline BMI z-score explained up to 50% of variance in response at ultimate visit.
Clinic-based interventions improve weight status. Baseline variables predict only a small proportion of response; response at the first visit is a more meaningful tool to guide clinical decisions.
PMCID: PMC2921937  PMID: 19960890
obesity; insulin; lifestyle counseling; adolescents; weight loss
7.  The Laminin–Nidogen Complex is a Ligand for a Specific Splice Isoform of the Transmembrane Protein Tyrosine Phosphatase LAR  
The Journal of Cell Biology  1998;141(7):1675-1684.
Leukocyte antigen–related protein (LAR) is a prototype for a family of transmembrane protein tyrosine phosphatases whose extracellular domain is composed of three Ig and several fibronectin type III (FnIII) domains. Complex alternative splicing of the LAR-FnIII domains 4–8 has been observed. The extracellular matrix laminin–nidogen complex was identified as a ligand for the LAR-FnIII domain 5 (Fn5) using a series of GST-LAR-FnIII domain fusion proteins and testing them in in vitro ligand-binding assays. LAR– laminin–nidogen binding was regulated by alternative splicing of a small exon within the LAR-Fn5 so that inclusion of this exon sequence resulted in disruption of the laminin–nidogen-binding activity. Long cellular processes were observed when HeLa cells were plated on laminin–nidogen, but not when plated on a fibronectin surface. Indirect immunofluorescent antibody staining revealed high expression of LAR in a punctate pattern, throughout the length of these cellular processes observed on laminin–nidogen. Antibody-induced cross-linking of LAR inhibited formation of these cellular processes, and inhibition was correlated with changes in cellular actin cytoskeletal structure. Thus, LAR–laminin–nidogen binding may play a role in regulating cell signaling induced by laminin–nidogen, resulting in cell morphological changes.
PMCID: PMC2133008  PMID: 9647658

Results 1-7 (7)