The effects of weight loss on FABP4 and RBP4 in obese women with metabolic syndrome.

Fat accumulation is associated with the release of many novel adipokines such as retinol-binding protein 4 and fatty acid-binding protein 4. These adipokines have been linked to insulin resistance, metabolic syndrome, type 2 diabetes and cardiovascular disease. Since weight loss is the first step for the treatment of metabolic syndrome, which increases the risks for both type 2 diabetes and cardiovascular disease, we have investigated the effects of weight loss on serum retinol-binding protein 4 and fatty acid-binding protein 4 in obese individuals with this syndrome. Twenty-nine obese female subjects with metabolic syndrome, aged 18-62 years completed a 2-month weight loss diet plan. Data were collected from dual-energy X-ray absorptiometry and indirect calorimetry. Blood was taken at baseline and at 2 months and assayed for adipokines, lipids, and insulin resistance parameters. The change in circulating fatty acid-binding protein 4 levels were inversely correlated with total weight loss (p<0.02) and lean mass loss (p<0.01), but not with fat mass loss. Retinol-binding protein 4 levels did not track with any measure of body composition. Changes in leptin levels were found to correlate with weight loss (p<0.02), fat loss (p<0.03), and lean mass loss (p<0.05). Fatty acid-binding protein 4 levels increased and retinol-binding protein 4 levels did not change during moderate weight loss in obese women with metabolic syndrome; however, several other risk factors for type 2 diabetes and cardiovascular disease did improve with weight loss.

Phosphoinositide 3-kinase modulation of beta(3)-integrin represents an endogenous "braking" mechanism during neutrophil transmatrix migration.

During episodes of inflammation, neutrophils (polymorphonuclear leukocytes [PMNs]) encounter subendothelial matrix substrates that may require additional signaling pathways as directives for movement through the extracellular space. Using an in vitro endothelial and epithelial model, inhibitors of phosphoinositide 3-kinase (PI3K) were observed to promote chemoattractant-stimulated migration by as much as 8 +/- 0.3-fold. Subsequent studies indicated that PMNs respond in a similar manner to RGD-containing matrix substrates and that PMN-matrix interactions are potently inhibited by antibodies directed against beta(3)- but not beta(1)-integrin antibodies, and that PI3K inhibitors block beta(3)-integrin dependence. Biochemical analysis of intracellular beta(3)-integrin uncoupling by PI3K inhibitors revealed diminished beta(3)-integrin tyrosine phosphorylation and decreased association with p72(syk). Similarly, the p72(syk) inhibitor piceatannol promoted PMN transmatrix migration, whereas HIV-tat peptide-facilitated loading of peptides corresponding to the beta(3)-integrin cytoplasmic tail identified the functional tyrosine residues for this activity. These data indicate that PI3K-regulated beta(3)-integrin represents a natural "braking" mechanism for PMNs during transit through the extracellular matrix.

Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia.

Mucosal organs such as the intestine are supported by a rich and complex underlying vasculature. For this reason, the intestine, and particularly barrier-protective epithelial cells, are susceptible to damage related to diminished blood flow and concomitant tissue hypoxia. We sought to identify compensatory mechanisms that protect epithelial barrier during episodes of intestinal hypoxia. Initial studies examining T84 colonic epithelial cells revealed that barrier function is uniquely resistant to changes elicited by hypoxia. A search for intestinal-specific, barrier-protective factors revealed that the human intestinal trefoil factor (ITF) gene promoter bears a previously unappreciated binding site for hypoxia-inducible factor (HIF)-1. Hypoxia resulted in parallel induction of ITF mRNA and protein. Electrophoretic mobility shift assay analysis using ITF-specific, HIF-1 consensus motifs resulted in a hypoxia-inducible DNA binding activity, and loading cells with antisense oligonucleotides directed against the alpha chain of HIF-1 resulted in a loss of ITF hypoxia inducibility. Moreover, addition of anti-ITF antibody resulted in a loss of barrier function in epithelial cells exposed to hypoxia, and the addition of recombinant human ITF to vascular endothelial cells partially protected endothelial cells from hypoxia-elicited barrier disruption. Extensions of these studies in vivo revealed prominent hypoxia-elicited increases in intestinal permeability in ITF null mice. HIF-1-dependent induction of ITF may provide an adaptive link for maintenance of barrier function during hypoxia.

HIV & breastfeeding: a model for sensitive midwifery.

The following article forms part of an overall submission which assisted the author in winning the 1996 Victorian Irving Buzzard Prize. It explores important present day issues of HIV and Breastfeeding and provides an overview of a developed Model designed to help the Midwife sensitively and informatively assist the HIV positive mother in all facets of her decision making regarding infant feeding, and many other associated issues.